PHACE Syndrome Research Articles

Individualized approach for Coarctation of the Aorta in a Patient with PHACE syndrome and Extensive Hemangiomas

PHACE syndrome is a neurocutaneous disorder with large facial segmental hemangiomas associated with anomalies of the brain, eye and heart. We report a case of a 3 years old girl who presented at the age of 6 weeks with severe coarctation of the aorta and aortic arch aneurysm. In addition, she had extensive strawberry hemangiomas over the scalp, neck and chest which, after extensive investigation, led to the diagnosis of PHACE syndrome. After complete evaluation we successfully initiated treatment with propranolol that was pursued without complications over three years with striking success and remarkable regression of her hemangiomas. Meanwhile the coarctation was managed conservatively. This case highlights that propranolol treatment, while effective against hemangiomas, may contribute to slow the progression of aortic arch aneurysm and delay the need for high risk surgical intervention.

STERNAL CLEFT AND SEGMENTAL FACIAL HEMANGIOMAS IN CHILDREN WITH PHACES SYNDROME: EFFECTIVENESS AND SAFETY OF CONSERVATIVE MANAGEMENT AND SURGICAL CORRECTION

The aim is to determine the risk factors of sternal cleft and segmental facial hemangiomas association in children with PHACES syndrome. Materials and methods: 32 inpatient children with segmental facial hemangiomas and 19 children with sternal cleft were investigated concerning the Metry criteria of PHACES syndrome. Results: In 6 children PHACE syndrome was diagnosed. Patients with bilateral S3 hemangiomas (50%, 3/6) had airway involvement with respiratory disorders. Conservative treatment was propranolol monotherapy (66.7%, 4/6), or combination of prednisolone and propranolol (33.3%, 2/6). Duration of propranolol treatment in children with PHACES syndrome was on an average 24.25 ± 4.49 months exceeding the duration of propranolol therapy in children with isolated soft tissue lesions (p<0.05). Primary surgical treatment of sternal cleft performed in children aged 2 (n=3) and 4 (n=1) months. The later period of surgery associated with the localization of hemangioma in the surgery region. Primary repair of sternal cleft was completed successfully in all cases; partial resection of the thymus made closure easier. Conclusions: Primary surgical correction of a sternal cleft performed in young children provides good results. Partial resection of the thymus prevents respiratory and cardiovascular complications. Preoperative propranolol treatment averts the hemorrhagic complications in children with hemangiomas in surgical region.

Morning glory disc anomaly associated with large facial infantile hemangioma as the presenting signs of PHACE syndrome.

Infantile hemangioma, the most common benign tumor in infancy, is usually an isolated condition occurring in many different locations in the body. However, large infantile hemangioma may be associated with other systemic malformations, including central nervous system, cerebrovascular, cardiac, and ophthalmology abnormalities, a condition termed PHACE syndrome. In this paper, we describe a case of PHACE syndrome that was presented with the unique association of a large facial infantile hemangioma and morning glory anomaly.

Hamartomas and midline anomalies in association with infantile hemangiomas, PHACE, and LUMBAR syndromes.

The pathogenesis of infantile hemangiomas (IH), PHACE, and LUMBAR syndromes remains unknown. We aim to describe histopathologic features of midline anomalies associated with IH, including patients with PHACE and LUMBAR syndromes. A multicenter retrospective chart review was performed to identify patients with IH, PHACE, and LUMBAR syndrome with histopathologic specimens from sternal or midline anomalies. A total of 18 midline lesions from 13 patients were included. Out of 18, 14 midline lesions underwent both histopathologic and clinical review. Three hamartoma-like chin plaques and one supraumbilical raphe underwent only clinical review. All 13 patients had midline lesions and IH. Histopathologic diagnoses were as follows: rhabdomyomatous mesenchymal hamartoma (3), folliculosebaceous cystic hamartoma (1), fibroepithelial polyp (1), verrucous epidermal hyperplasia with vascular proliferation and fibroplasia (1), congenital midline cervical cleft (1), pericardium with fibrosis (1), fibrous components with increased collagen (1), atrophic skin/membrane (3), angiolipomatous mass with neural components (1), and lipomatous mass (1). Due to the retrospective nature of this study, it was not possible to obtain pathology slides for all midline lesions that had previously been biopsied or resected. We show clinically and histopathologically a new association between PHACE syndrome and rhabdomyomatous mesenchymal hamartoma (RMH), in addition to demonstrating the association between PHACE syndrome and chin hamartomas. We also display histopathologic findings seen in midline lesions resected from LUMBAR patients. Rhabdomyomatous mesenchymal hamartoma is thought to be related to aberrations of mesenchymal cells during development; therefore, this may provide clues to the pathogenesis of IH and related syndromes.

Dieulafoy lesions and PHACE syndrome

Dieulafoy's lesion (DL) is a small gastrointestinal (GI) mucosal erosion due to an abnormally large caliber and persistent submucosal arteriole. Typically occurring in adults, they are an extremely rare cause of GI bleeding in pediatrics. We report a case of multiple jejunal DLs in a 9-year-old girl with posterior fossa brain malformations, hemangiomas, arterial lesions, cardiac abnormalities, eye abnormalities (PHACE) syndrome, and the first described use of rapamycin in the treatment of pediatric DLs.

Endocrine manifestations of PHACE syndrome.

PHACE syndrome is an uncommon disorder of posterior fossa anomalies, cervicofacial infantile hemangiomas, arterial anomalies, cardiac defects, eye anomalies, and midline/ventral defects. Endocrine abnormalities including hypopituitarism and ectopic thyroid were rarely described. In this article we review occurrence, onset, presenting symptoms, hormonal treatments and outcomes of all endocrine abnormalities in PHACE syndrome. Eleven of 20 (55%) had hypothalamic-pituitary dysfunction and 10 of 20 (50%) had thyroid dysgenesis. A thorough understanding of the endocrine manifestations is important for clinicians to early identify endocrine involvement in PHACE and develop plans for monitoring and treatment of its complications.

Natural history of PHACE syndrome: A survey of adults with PHACE.

Awareness of PHACE syndrome has increased; however, little information exists regarding its natural history, especially in patients over the age of 18. We aim to describe the natural history of PHACE to enhance clinical management and counseling of patients. A cohort of patients ≥18years was identified through the PHACE Syndrome Registry and a Vascular Anomalies Clinic Database. A cross-sectional survey was designed after a review of the literature by PHACE experts (IF, JP, DS). Questions were selected by consensus, and the survey was conducted using the Qualtrics platform and via in-person interviews. A 75% response rate was found. Eighteen adults-17 females and one transgender male-completed the survey. Respondents ranged in age from 18 to 59, with 24 being the mean age. Eighty-nine percent reported experiencing headaches, and 17% reported experiencing acute but transient symptoms mimicking acute ischemic stroke, later diagnosed as atypical migraines. Thirty-three percent reported hearing loss, and 67% endorsed dental issues. One patient experienced two arterial dissections. Three-fourths who attempted conception were successful, and none of their children had clinical features of PHACE. Because results were based on a retrospective survey, data captured were prone to recall bias and not objective. Results were limited by a small sample size. Health care providers should be aware of a possible increased risk of neurovascular complications, including atypical migraines mimicking transient ischemic attacks and arterial dissection, in adults with PHACE. Heritability has not been demonstrated, and future studies are needed to assess the risk of infertility.

Precursor of hemangioma: the diagnosis is not always easy.

At birth, the differential diagnosis between salmon patch, port-wine stain, hemangioma precursor and capillary malformation / arteriovenous malformation is important because it is necessary to pronounce on the regression or not of the lesions, on the possible investigations to do, on the prognosis and on the type of therapeutic approach. However, the diagnosis between these very different entities is not always easy. The most common mistake is to diagnose port-wine stain, to realize after a few days that it is instead a segmental hemangioma or a PHACE syndrome. The dermoscopic examination is not easy to perform in the newborn due to its continuous movement and is not always decisive (2); the presence of coarse and irregular telangiectasias (1) favors the diagnosis of hemangioma. In doubtful cases it is wise to wait a few days before communicating the definitive diagnosis.

Pituitary Lesion in a Neonate

Summary The patient is a term girl who presented at 2 weeks of age with a large segmental facial hemangioma without PHACE syndrome (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, and eye anomalies). Magnetic resonance imaging (MRI) at 3 months of age (FIG 1) showed a pituitary hemangioma characterized by an enhancing, T1 isointense, T2 hyperintense sellar/suprasellar mass without susceptibility or diffusion restriction. The patient underwent a course of treatment with oral propranolol, which has previously been shown to be an effective treatment for intracranial hemangiomas. 1 Repeat imaging (FIG 2) after 9 months of treatment showed decreased size of the sellar/suprasellar mass with persistent enhancement.

Surgery on a dilated aorta associated with a connective tissue disease or inflammatory vasculitis in children and adolescents.

This research investigated patients who underwent surgery for a dilated aorta associated with a connective tissue disease or inflammatory vasculitis in children and adolescents. The medical records of 11 patients who underwent aortic surgery for dilatation resulting from a connective tissue disease or inflammatory vasculitis between 2000 and 2017 were retrospectively reviewed. The median age and body weight of the patients were 9.6 years (range 5.4 months-15.5 years) and 25.8 kg (range 6.8-81.5), respectively. The associated diseases were Marfan syndrome (n = 3), Loeys-Dietz syndrome (n = 3), Kawasaki disease (n = 1), Takayasu arteritis (n = 1), PHACE syndrome (n = 1), tuberous sclerosis (n = 1), and unknown (n = 1). The most common initially affected area was the ascending aorta. During the 66.4 ± 35.9 months of follow-up, two Marfan syndrome patients died, and four patients (one Marfan syndrome and three Loeys-Dietz syndrome) had repeated aortic operation. Except for one patient, the functional class was well maintained in all patients who were followed up. Cases of surgical treatment for a dilated aorta associated with a connective tissue disease and inflammatory vasculitis are rare in children and adolescents at our institution. Most of the patients in this study showed a tolerable postoperative course. However, the aorta showed progressive dilation over time even after surgical treatment, especially in patients with Loeys-Dietz syndrome. In these patients, close and more frequent regular follow-up is required.

Dental root abnormalities in four children with PHACE syndrome

PHACE(S) syndrome is a condition characterized by posterior fossa malformations, hemangiomas, arterial anomalies, cardiac defects, eye abnormalities, sternal cleft, and supraumbilical raphe. We present four children with PHACE(S) syndrome who have absence of or severe malformation of the roots of their permanent first molars (PFMs). Root abnormalities in the children's molars were bilateral and not restricted to the segments affected by cutaneous hemangioma. The reason for root abnormalities is unknown, but given the rarity of these findings in healthy children, it is likely an additional dental manifestation of PHACE syndrome. The absence of functional roots in the PFMs can result in significant consequences. Therefore, we recommend a panoramic dental radiograph during transitional dentition for children with PHACE syndrome to screen for dental root abnormalities.

Moyamoya syndrome and PHACE syndrome: clinical and radiographic characterization of the intracranial arteriopathy and response to surgical revascularization.

PHACE syndrome (PHACES) has been linked to cervical and cerebral vascular anomalies, including persistent embryonic anastomoses and progressive steno-occlusive disease. However, no prior studies have documented the long-term response of PHACES patients with moyamoya disease to surgical revascularization with pial or myosynangiosis. The authors present their experience with 8 consecutive patients with PHACES and moyamoya disease. Retrospective review of patients who underwent pial synangiosis revascularization for moyamoya disease with concurrent diagnosis of PHACES. A total of 8 patients out of 456 surgically treated moyamoya patients had a diagnosis of PHACES. All patients were female, and their average age at the time of surgical treatment was 9.3 years (range 1.8-25.8 years). Five patients had associated basilar artery anomalies or stenosis. All patients had symptomatic narrowing of the petrous segment of the internal carotid artery with tortuous collateralization. Three patients underwent unilateral pial or myo-synangiosis and 5 underwent bilateral procedures. The average hospital length of stay was 5.0 days (range 3-7 days). There were no postoperative complications. Follow-up ranged from 8 to 160 months (average 56 months). Seven of 8 patients have had follow-up angiograms and all had Matsushima grade A or B collateralization without progression of stenosis in other locations. All patients had reduced cortical FLAIR signal on 6-month follow-up MRI and no evidence of new radiographic or clinical strokes. Patients with moyamoya disease and PHACES had an intracranial arteriopathy characterized by ectactic anterior vasculature with concomitant basilar artery stenosis, and were all female. The patients had both radiographic and clinical responses to pial synangiosis. The surgical treatment of these patients can be challenging given facial hemangiomas located near the surgical field. Patients with unilateral disease did not have evidence of progression in other cerebral circulation during the given follow-up period.

Persistent stapedial artery in PHACE syndrome

IntroductionPHACE syndrome is characterized by posterior fossa malformations, haemangioma, arterial anomalies, coarctation of the aorta, and eye abnormalities. Case reportWe present the case of a 6-year-old girl followed since birth for PHACE syndrome and left hemifacial haemangioma, who presented with left hearing loss. Computed tomography scan showed left persistent stapedial artery (PSA). DiscussionTwo types of arterial anomalies may be observed in PHACE syndrome: persistence of embryonic arteries and anomalies of cerebral arteries. PSA can be observed in the context of PHACE syndrome. Children with PHACE syndrome require regular audiometric follow-up to detect hearing loss and avoid its consequences on speech and language development.

PHACES syndrome – A rare case report

PHACES syndrome stands for posterior fossa malformations–hemangioma–arterial anomalies–cardiac defects–eye abnormalities–sternal cleft all together known as “PHACES syndrome.” It is a rare cutaneous condition characterized by multiple congenital abnormalities. It affects girls nine times more often than boys. A 3-year-old girl presented with hemangioma of the face, palate, lips, and eyelids and developmental delay associated with seizure episodes. In the ocular examination, congenital cataract, choroidal coloboma, and optic disc hypoplasia were seen. Systemically, there were sternal cleft, ventricular septal defect, and posterior fossa arachnoid cyst and central nervous system vascular abnormalities. Diagnosis was made from systemic examination and ocular examination along with imaging study of the head and chest. PHACES syndrome needs to be managed by a multidisciplinary team of experts such as cardiologist, ophthalmologist, neurologist, and neurosurgeon. Every child with PHACES syndrome should be evaluated for glaucoma and associated pituitary function at each visit.

Large Infantile Hemangioma on the Face: Let’s ‘PHACE’ It

Background: Infantile hemangiomas (IH) are the most common benign (vascular) tumors in infancy but due to their natural self-limiting course do not necessarily need treatment; in case of ulceration, bleeding or potential deformity, treatment is necessary. Large segmental facial hemangiomas may be associated with PHACE syndrome. Case presentation: We present a case of a boy with a large segmental facial IH. Ulceration, size and location were indications for starting propranolol up to a dose of 3 mg/kg/day in three doses, eleven days after birth. Because of the location and distribution, PHACE syndrome had to be excluded: the patient was checked for possible brain, cardiac and vascular malformations and visual impairment. The IH improved. At the age of nine months, there were no adverse effects or IH progression. Discussion: Propranolol is a beta-blocker effective in treating IH. Its working mechanism has not been completely clarified. We provide a thorough description of our approach to the early propranolol treatment of this large segmental facial IH. Conclusion: Complicated IH like the one described here can be treated safely and effectively with propranolol; very early treatment initiation is recommended to prevent the development of anatomic deformities. Our patient was treated with propranolol 3 mg/kg/day in three doses in order to prevent future disfigurement when it is located in a high-risk area like the face. Further research is needed to create a uniform approach and universal guideline for the treatment of IH with propranolol.

PHACE syndrome: Infantile hemangiomas associated with multiple congenital anomalies: Clues to the cause.

Infantile hemangiomas (IH) are the most common vascular tumor of infancy with an estimated 80,000 annual diagnoses in the United States. The genetic mechanisms underlying IH and the related multi-organ birth defect syndromes, PHACE (an acronym for Posterior fossa brain malformations, segmental facial Hemangiomas, Arterial anomalies, Cardiac defects, Eye anomalies, and sternal clefting or supraumbilical raphe) and LUMBAR (an acronym for Lower body hemangiomas, Urogenital anomalies, Myelopathy, Bone deformities, Anorectal malformations/Arterial anomalies, Renal anomalies) remain unsolved. With advances in next generation sequencing (NGS), genomic alterations have been identified in a wide range of vascular anomaly syndromes. We hypothesize that PHACE is a genetic disorder, caused by somatic mutations, likely in cancer genetic pathways. Identification of the genetic etiology will lead to improved diagnosis in PHACE syndrome and development of targeted therapies for IH and related congenital anomalies.

Unsolved recognizable patterns of human malformation: Challenges and opportunities.

Due to the efforts of the clinical and scientific communities and boosted by recent advances in genetic technologies, we now understand the molecular mechanisms underlying most of the frequent and recognizable human malformation syndromes. However, some well-established human malformation syndromes remain without a molecular diagnosis despite intensive investigation. This issue of Seminars mines the phenotypic entries in OMIM and estimates that of the documented 2,034 unsolved entries likely to represent a rare genetic disease, only 160 are well-established and possibly amenable to investigation. This issue also reviews well-characterized and extensively investigated human malformation syndromes and associations that remain unsolved, including the following: Dubowitz syndrome (MIM 223370%), Hallermann-Streiff syndrome (MIM 234100%), PHACE syndrome (MIM 606519), Oculocerebrocutaneous syndrome (MIM 164180), Aicardi syndrome (MIM 304050%), Gomez-Lopez-Hernandez syndrome and Rhombencephalosynapsis (MIM 601853%), VACTERL (MIM 192350%), and Nablus syndrome (MIM #608156). Possible explanations for their intractability to molecular diagnosis are explored, including genetic and phenotypic heterogeneity, mosaicism, epigenetics, gene-environment interactions, and other non-Mendelian contributions. Finally, this issue of Seminars presents a path forward for these unsolved rare conditions and suggests a renewed focus on solving amendable OMIM disorders. It is clear that the way forward will require new technologies, global cooperation, and data sharing; these will also be necessary to help reach the vision of the International Rare Diseases Research Consortium (IRDiRC), that is to enable all people living with a rare disease to receive an accurate diagnosis, care and available therapy within 1 year of coming to medical attention.

Ocular Complications in PHACE Syndrome: A True Association or a Coincidence?

To characterize the risk for ocular complications in patients with PHACE syndrome. This study included consecutive patients with PHACE syndrome who were seen at Lurie Children's Hospital of Chicago from January 2000 through May 2017. A complete ophthalmic examination was performed in all patients, with extra attention for findings typically associated with PHACE syndrome. Thirty patients (67% female, median age of onset 0.08 months) were included: 38 (93%) demonstrated a segmental infantile hemangioma distribution. Twenty-one (70%) cases had a periocular involvement, and 47% had an infantile hemangioma with a deep component. Among 21 patients with periocular distribution, 9 had ocular complications secondary to the periocular location (mainly ptosis, nasolacrimal duct obstruction, and refractive errors), and one had an ocular complication specifically associated with PHACE syndrome (Horner syndrome). None of the patients without periocular distribution had an ocular complication. In patients with PHACE syndrome who have a periocular infantile hemangioma, a complete eye examination is recommended. Although specific ocular anomalies related to PHACE syndrome are rare, serious ocular complications secondary to the location of the hemangioma may be present. Eye examination in patients with PHACE syndrome without a periocular infantile hemangioma distribution is likely of low yield.

Oral propranolol in the treatment of proliferating infantile haemangiomas: British Society for Paediatric Dermatology consensus guidelines.

Infantile haemangiomas (IH) are the most common vascular tumours of infancy. Despite their frequency and potential complications, there are currently no unified U.K. guidelines for the treatment of IH with propranolol. There are still uncertainties and diverse opinions regarding indications, pretreatment investigations, its use in PHACES (posterior fossa malformations-haemangiomas-arterial anomalies-cardiac defects-eye abnormalities-sternal cleft and supraumbilical raphe) syndrome and cessation of treatment. To provide unified guidelines for the treatment of IH with propranolol. This study used a modified Delphi technique, which involved an international treatment survey, a systematic evidence review of the literature, a face-to-face multidisciplinary panel meeting and anonymous voting. The expert panel achieved consensus on 47 statements in eight categories, including indications and contraindications for starting propranolol, pretreatment investigations, starting and target dose, monitoring of adverse effects, the use of propranolol in PHACES syndrome and how to stop treatment. These consensus guidelines will help to standardize and simplify the treatment of IH with oral propranolol across the U.K. and assist in clinical decision-making.

The cerebellar “tilted telephone receiver sign” enables prenatal diagnosis of PHACES syndrome

To describe a unique posterior fossa neuroimaging characteristic of prenatal PHACES syndrome (PS): unilateral cerebellar hypoplasia (UCH) and ipsilateral posterior fossa (PF) cyst communicating with an asymmetrically distended 4th ventricle. The registries of seven prenatal diagnosis centers were searched for cases with PF findings and a postnatal diagnosis of PS. All records were evaluated for ultrasound and MRI findings and the postnatal outcome. PS was diagnosed after birth according to the consensus statement on diagnostic criteria for PS from 2009. The imaging findings of the PS fetuses were compared to a group of consecutive cases with fetal UCH, whose postnatal diagnosis was not PS. The PS group included 10 fetuses. All were referred due to UCH accompanied by an ipsilateral retrocerebellar cyst. All pregnancies resulted in livebirths, all newborns had a large segmental facial hemangioma. In all PS fetuses the affected cerebellar hemisphere was upwardly displaced by an ipsilateral PF cyst communicating with an asymmetrically distended 4th ventricle. An upwardly rotated and deviated vermis merged with the contralateral cerebellar peduncles forming an elongated oblique connection between the cerebellar hemispheres, resulting in a unique cerebellar shape, "a tilted telephone receiver sign" (TTRS), on the coronal plane through the upper vermis.The non-PS group included 11 fetuses with UCH: clastic cerebellar lesions (8) and a unilateral PF arachnoid cyst (3). The TTRS was not depicted in any of them (p<0.0005). The cerebellar TTRS is a specific fetal imaging feature of PHACES syndrome enabling its prenatal diagnosis.