Encephalocraniocutaneous Lipomatosis: A Case Report.

ABSTRACT: Encephalocraniocutaneous lipomatosis (ECCL) is a rare congenital syndrome and subclassification of oculoectodermal syndrome. Encephalocraniocutaneous lipomatosis may be associated with postzygotic mutations. However, absence of an identifiable mutation does not preclude a diagnosis of ECCL. Encephalocraniocutaneous lipomatosis commonly causes skin, eye, and central nervous system anomalies. Diagnosis can be made through genetic sequencing or standardized clinical criteria. One clinically apparent major criterion for the diagnosis of ECCL is nevus psiloliparus (NP), a fatty nevus with overlying nonscarring alopecia. In this case, a 50-day-old female infant with uncomplicated birth history presented to dermatology clinic for evaluation of 2 superficial cranial masses that had been present since birth without regression or evolution. One of the masses was located within the hairline and demonstrated overlying nonscarring alopecia, suspicious of NP. Because of concern for ECCL, brain magnetic resonance imaging was ordered and revealed 2 intracranial lipomas. Genetic testing was inconclusive. Excision of the masses was performed at the request of the parents for cosmetic purposes. Histologic evaluation of the surgical specimens confirmed the diagnosis of NP and ECCL. A suspected NP should raise concern for ECCL and prompt further evaluation for systemic involvement. In particular, patients with suspected ECCL should be screened for ocular and CNS involvement. Early identification and diagnosis are important for prognostication because patients with ECCL are at increased risk of developing neoplasms of the head and neck and may require more frequent screening examinations.

Non-vascular intracranial lesions in three children with PHACE association.

PHACE (posterior fossa malformations, hemangiomas, arterial anomalies, cardiac anomalies, eye anomalies) association has many recognized clinical features. A link between PHACE and non-vascular intracranial lesions has not been well-described. We report three pediatric patients with PHACE and non-vascular intracranial lesions.

PHACE(S) SYNDROME - EARLY DIAGNOSTICS IN THE MAXILLOFACIAL AREA.

OBJECTIVE: The aim: To determine the minimum criteria for early diagnosing PHACE(S) syndrome in neonates and infants with infantile hemangioma (IH) in the max¬illofacial area. PATIENTS AND METHODS: Materials and methods: A total of 26 asymptomatic children from 20 days to six months of aged with IH of more than 5 cm² in the maxillofacial area were included in this study. A medical record of patients clinical examination, Holter monitoring, echocardiographic ultrasound and magnetic resonance imaging (MRI) were analysed. The IH treatment with ß-blockers was carried out. RESULTS: Results: IH localization was diagnosed: 62% with a lesion of a part facial segment, 23% in one segment, 15% in several segments (p=0.018), and 12% with other parts of the body lesion (p=1.000). The patent foramen ovale was diagnosed in 35% of children. Central nervous system disorders were observed in 12% over two years of age. The indices of Holter monitoring and blood glucose changed in age norm range during treatment. Cardiovascular (the aortic coarctation (p=0.003) and brain (the Dandy-Walker malformation) (p=0.031) abnormalities were determined in two cases (8%) according to the MRI only. We diagnosed PHACE(S) syndrome in both these cases of children, only aged 12 months and 2.5 years old. CONCLUSION: Conclusions: Early diagnosis of PHACE(S) syndrome is possible on a contrast-enhanced MRI performed in asymptomatic neonates and infants with the facial several segmental IH with / without ulceration (p=0.018, p=0.046; p < 0.05) for recognition of presymptomatic cardiovascular and brain abnormalities.

Long-term follow-up of patients with extensive segmental infantile hemangioma of the cervical or facial region: A French single-center prospective study.

BACKGROUND: Infantile hemangiomas (IHs) can be part of PHACE (posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies, eye anomalies) syndrome when they are segmental, extensive, and located on the face or neck. The initial assessment is codified and well known, but there are no recommendations for the follow-up of these patients. The aim of this study was to assess the long-term prevalence of different associated abnormalities. METHODS: Patients with a history of large segmental IHs of the face or neck. diagnosed between 2011 and 2016 were included in the study. Each patient underwent an ophthalmological, dental, ENT (ear, nose, and throat), dermatological, neuro-pediatric, and radiological assessment at inclusion. Eight patients including five with PHACE syndrome were prospectively evaluated. RESULTS: After a mean follow-up of 8.5 years, three patients presented with an angiomatous aspect of the oral mucosa, two with hearing loss, and two with otoscopic abnormalities. No patients developed ophthalmological abnormalities. The neurological examination was altered in three cases. Brain magnetic resonance imaging follow-up was unchanged in three out four patients and revealed atrophy of the cerebellar vermis in 1 patient. Neurodevelopmental disorders were found in five of the patients and learning difficulties were observed in five patients. The S1 location appears to be associated with a higher risk of neurodevelopmental disorders and cerebellar malformations, while the S3 location was associated with more progressive complications, including neurovascular, cardiovascular, and ENT abnormalities. CONCLUSION: Our study reported late complications in patients with a large segmental IH of the face or neck, whether associated with PHACE syndrome or not, and we proposed an algorithm to optimize the long-term follow-up.

PHACES-like syndrome with TMEM260 compound heterozygous variants.

PHACES syndrome is a multiple congenital disorder with unknown etiology that is characterized by Posterior fossa anomalies, Hemangioma, Arterial lesions, Cardiac abnormalities/coarctation of the aorta, Eye anomalies, and Sternal cleft. Compound heterozygous or homozygous TMEM260 variants cause structural heart defects and renal anomalies syndrome (SHDRA). We describe a 10-year-old male patient with a PHACES-like syndrome and TMEM260 compound heterozygous variants who demonstrated overlapping phenotypes between the two syndromes. He presented with truncus arteriosus, supraumbilical raphe, ophthalmological abnormality, vertebral abnormality, borderline intellectual disability, and hearing loss. He had normal serum creatinine. In proband exome sequencing, compound heterozygous TMEM260 variants (NM_017799.4 c.1617delG p.(Trp539Cysfs*9)/c.1858C > T p.(Gln620*)) were identified. Twelve patients have been reported with TMEM260-related SHDRA: 10 had truncus arteriosus and 6 had renal failure. One previously reported patient had facial port wine nevus and another patient had supraumbilical raphe, which are the cardinal signs for PHACES syndrome. TMEM260-related SHDRA could share overlapping clinical features with PHACES syndrome. This report expands the phenotypic spectrum of a TMEM260-related disorder.

PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma.

Phakomatosis pigmentovascularis is a diagnosis that denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement, including CNS disease, asymmetrical growth, and a predisposition to malignancy. Using a tight phenotypic group and high-depth next-generation sequencing of affected tissues, we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of phakomatosis pigmentovascularis type III or spilorosea. Within an individual, the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood. We go on to show that the same variants can cause either the pigmentary or vascular phenotypes alone, and drive melanoma development within pigmentary lesions. Protein structure modeling highlights that although variants lead to loss of function at the level of the phosphatase domain, resultant conformational changes promote longer ligand binding. In vitro modeling of the missense variants confirms downstream MAPK pathway overactivation and widespread disruption of human endothelial cell angiogenesis. Importantly, patients with PTPN11 mosaicism theoretically risk passing on the variant to their children as the germline RASopathy Noonan syndrome with lentigines. These findings improve our understanding of the pathogenesis and biology of nevus spilus and capillary malformation syndromes, paving the way for better clinical management.

Snapshots from within the cell: Novel trafficking and non trafficking functions of Snap29 during tissue morphogenesis.

Membrane trafficking is a core cellular process that supports diversification of cell shapes and behaviors relevant to morphogenesis during development and in adult organisms. However, how precisely trafficking components regulate specific differentiation programs is incompletely understood. Snap29 is a multifaceted Soluble N-ethylmaleimide-sensitive factor Attachment protein Receptor, involved in a wide range of trafficking and non-trafficking processes in most cells. A body of knowledge, accrued over more than two decades since its discovery, reveals that Snap29 is essential for establishing and maintaining the operation of a number of cellular events that support cell polarity and signaling. In this review, we first summarize established functions of Snap29 and then we focus on novel ones in the context of autophagy, Golgi trafficking and vesicle fusion at the plasma membrane, as well as on non-trafficking activities of Snap29. We further describe emerging evidence regarding the compartmentalisation and regulation of Snap29. Finally, we explore how the loss of distinct functions of human Snap29 may lead to the clinical manifestations of congenital disorders such as CEDNIK syndrome and how altered SNAP29 activity may contribute to the pathogenesis of cancer, viral infection and neurodegenerative diseases.

Hemangioma Genetics and Associated Syndromes.

This article explores what is known regarding infantile hemangioma (IH) genetics. Despite a great deal of research on this topic, the relationship between IH genetics and pathogenesis has yet to be understood. This article also outlines the appropriate work-up and management of syndromes associated with specific presentations of IH.

Expending the Phenotypic Spectrum of Encephalocraniocutaneous Lipomatosis: About a Prenatal Case With Complete Autopsy.

Encephalocraniocutaneous lipomatosis (ECCL) or Haberland syndrome (MIM #613001) is a rare congenital neurocutaneous disorder. It is characterized by unilateral ocular, cutaneous and central nervous system anomalies. Key clinical features include hairless fatty tissue nevus of the scalp, choristoma of the eye and intraspinal and intracerebral lipomas. We report one of the first cases diagnosed after termination of pregnancy at 35 WG, including antenatal and post-mortem imaging, complete autopsy and genetic analysis. Prenatal ultrasound and MRI of the third trimester showed multifocal spinal lesions and left lateral cerebral ventriculomegaly with cerebral atrophy. Diagnosis of ECCL was suggested at complete autopsy which revealed nevus psiloliparus of the scalp, facial hamartomas and intracranial and spinal lipomas. In addition, our case also exhibited a cardiac rhabdomyoma and a multicystic dysplastic kidney, both never reported to date in this syndrome. ECCL was confirmed by the identification of a postzygotic FGFR1 mutation. We reviewed the literature and discuss the pathogenesis of this syndrome.

Phakomatoses and Endocrine Gland Tumors: Noteworthy and (Not so) Rare Associations.

Phakomatoses encompass a group of rare genetic diseases, such as von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1), tuberous sclerosis complex (TSC) and Cowden syndrome (CS). These disorders are due to molecular abnormalities on the RAS-PI3K-Akt-mTOR pathway for NF1, TSC and CS, and to hypoxia sensing for VHL. Phakomatoses share some phenotypic traits such as neurological, ophthalmological and cutaneous features. Patients with these diseases are also predisposed to developing multiple endocrine tissue tumors, e.g., pheochromocytomas/paragangliomas are frequent in VHL and NF1. All forms of phakomatoses except CS may be associated with digestive neuroendocrine tumors. More rarely, thyroid cancer and pituitary or parathyroid adenomas have been reported. These susceptibilities are noteworthy, because their occurrence rate, prognosis and management differ slightly from the sporadic forms. The aim of this review is to summarize current knowledge on endocrine glands tumors associated with VHL, NF1, TSC, and CS, especially neuroendocrine tumors and pheochromocytomas/paragangliomas. We particularly detail recent advances concerning prognosis and management, especially parenchyma-sparing surgery and medical targeted therapies such as mTOR, MEK and HIF-2 α inhibitors, which have shown truly encouraging results.

PHACES Syndrome and Associated Anomalies: Risk Associated With Small and Large Facial Hemangiomas.

OBJECTIVE. PHACES syndrome includes posterior fossa malformations, hemangioma, arterial anomalies, coarctation of the aorta and cardiac defects, eye abnormalities, and sternal defect with or without supraumbilical raphe. Usually, brain imaging is performed when facial hemangiomas are larger than 5 cm. Data on associated anomalies regardless of hemangioma size are sparse. The objective of this study was to determine, first, the prevalence of PHACES-like associated anomalies in a large sample of infants with all sizes of segmental facial or periorbital focal infantile hemangioma and, second, whether the cutaneous localization of the hemangioma correlates with the type of anomalies present. MATERIALS AND METHODS. The records of all patients of a vascular anomalies practice who had a diagnosis of segmental facial or periorbital focal infantile hemangioma and who had clinical photographs and brain MRI available were reviewed. The clinical photographs were reviewed to determine the localization by segment and lateralization. MRI was reviewed by two experienced pediatric radiologists. If present, cardiovascular anomalies, sternal defects, and eye anomalies were recorded. The criteria for definite and possible PHACES were used. RESULTS. The study included 122 children (90 girls, 32 boys; mean age, 16.6 months). Forty-five (36.9%) children had a facial infantile hemangioma larger than 5 cm. Twenty-two patients (18.0%) had PHACES or possible PHACES syndrome. Cerebrovascular structural anomalies were seen in 14 of 22 and brain anomalies in 6 of 22 patients with PHACES syndrome but in none and one of the patients in the group without PHACES (p < .001). Cardiovascular anomalies were seen in six patients and ocular anomalies in eight patients. All but one of them had PHACES syndrome. CONCLUSION. Clinical concern about associated extracutaneous anomalies is warranted for all children with facial segmental or periorbital focal infantile hemangiomas, including those with small hemangiomas. Further studies are needed to correlate cerebrovascular anomalies with the clinical evolution of hemangiomas and their effects on cerebral perfusion.

Tape stripping and lipidomics reveal skin surface lipid abnormity in female melasma.

The skin barrier of melasma is involved in the pathogenesis of melasma. Previous studies have shown that there are differences in the expression of epidermal lipid genes in melasma, but little is known about the epidermis lipid composition of melasma. Compared with the non-lesional skin, the content of total lipids, phosphatidic acid, phosphatidylserine, and ceramide (Cer) increased significantly in the lesional skin. Multivariate data analysis indicated that 40 individual Cer lipid species were responsible for the discrimination. In terms of acyl chain length in Cer, the expressions of very long chain (VLC) (C20-C26) and ultra-long chain (ULC) (>C26) increased significantly in the lesional skin. However, Cer[AH] had negative correlations with the activation of melanocytes in the lesional skin. Some lipid species had lower expression in lesional skin with high activation of melanocytes, as well as the high darkness. The epidermal thickness of lesional skin was higher compared with the non-lesional skin. These results suggest that Cer increased significantly in the lesional skin of melasma, possibly as a compensatory mechanism to maintain skin barrier function. Between different groups of darkness and activation of melanocytes, the change of ceramides might have correlation with the pigmentation progress of melasma.

Postzygotic inactivating mutation of KIF13A located at chromosome 6p22.3 in a patient with a novel mosaic neuroectodermal syndrome.

Hypomelanosis of Ito (HMI) is part of a neuroectodermal syndrome characterized by distinctive skin manifestations with or without multisystemic involvements. In our undiagnosed diseases program, we have encountered a 3-year-old girl presenting with characteristic skin hypopigmentation suggesting HMI and developmental delay. An exome and genome approach utilizing next-generation sequencing revealed a heterozygous de novo frameshift variant in the KIF13A gene, i.e., NM_022113.6: c.2357dupA, resulting in nonsense-mediated decay. The low mutant allelic ratio suggested that the mutation has occurred postzygotically leading to embryonic mosaicism. Functionally, K1F3A regulates cell membrane blebbing and migration of neural crest cells by controlling recycling of RHOB to the plasma membrane and is also involved in melanosome biogenesis. Importantly, hypopigmentation of the skin has been reported in chr 6p22.3-p23 microdeletion syndrome supporting the association of KIF13A haploinsufficiency with the novel neuroectodermal syndrome. With the increased availability of genome sequencing, we envisage more genetic causes of HMI will be identified in the future.

Neurocutaneous Melanocytosis and Leptomeningeal Melanoma.

Neurocutaneous melanocytosis (NCM) is a disorder characterized by multiple or large congenital nevi and excessive proliferation of melanocytes in the leptomeninges and brain parenchyma. The majority of NCM is a result of somatic mosaicism due to a single postzygotic mutation in codon 61 of NRAS. Patients with NCM are at high risk of developing leptomeningeal melanoma. The prognosis for leptomeningeal melanoma is poor with no known effective treatment options. We describe the clinical features, treatment, and outcome of 4 children with NCM and leptomeningeal melanoma and discuss the latest molecular findings and treatment options for this rare condition.

Arterial Spin-Labeling Perfusion for PHACE Syndrome.

BACKGROUND AND PURPOSE: Arterial stroke is a rare-but-reported complication in patients with posterior fossa brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities (PHACE) syndrome. Currently, stroke risk is inferred by the severity of arterial anomalies identified on MRA, though no evidenced-based data exist. The purpose of our study was to determine whether arterial spin-labeling MR imaging perfusion can detect alterations in CBF in patients with PHACE syndrome. MATERIALS AND METHODS: Records were reviewed from 3 institutions for all patients with PHACE syndrome who underwent arterial spin-labeling from 2000 to 2019. CBF was qualitatively investigated with arterial spin-labeling to determine whether there was decreased or normal perfusion. Arterial anomalies were characterized on MRA imaging, and parenchymal brain findings were evaluated on conventional MR imaging sequences. RESULTS: Forty-one patients with PHACE syndrome had arterial spin-labeling imaging. There were 30 females and 11 males (age range, 7 days to 15 years). Of the 41 patients, 10 (24%) had decreased CBF signal corresponding to a major arterial territory. Ten of 10 patients had decreased CBF signal in the anterior circulation, 2/10 had decreased anterior and posterior circulation CBF signal, 2/10 had decreased bilateral anterior circulation CBF signal, and 1/10 had globally decreased CBF signal. Forty of 41 (97.5%) patients had at least 1 arteriopathy, and in those with decreased CBF signal, the arteriopathy corresponded to the CBF signal alteration in 10/10 patients. CONCLUSIONS: Arterial spin-labeling can potentially characterize hemodynamic changes in patients with PHACE syndrome.