Postzygotic inactivating mutations of RHOA cause a mosaic neuroectodermal syndrome.

Hypopigmentation along Blaschko's lines is a hallmark of a poorly defined group of mosaic syndromes whose genetic causes are unknown. Here we show that postzygotic inactivating mutations of RHOA cause a neuroectodermal syndrome combining linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Our findings pave the way toward elucidating the etiology of pigmentary mosaicism and highlight the role of RHOA in human development and disease.

A case of PHACE syndrome with growth hormone deficiency and abnormal thyroid functions.

Background PHACE syndrome is a rare vascular neurocutaneous disorder characterized by posterior fossa anomalies, hemangioma, arterial anomalies, cardiac anomalies and eye anomalies. Growth hormone deficiency (GHD) has been infrequently described. Case presentation We report a girl with PHACE syndrome. Endocrine abnormalities including abnormal thyroid functions and GHD have recently been described in similar cases. Conclusions This case suggests the necessity to screen pituitary functions in all patients with PHACE syndrome with abnormal hypothalamus and pituitary (HP) anatomy. Likewise, growth parameters and thyroid function test (TFT) should be monitored in all patients with PHACE syndrome at regular intervals.

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.

BACKGROUND: 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. METHODS: A cohort of patients ≥ 18 years 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. RESULTS: 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. CONCLUSIONS: 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.

The tarsal plate manifestation of IgG4-related disease.

PURPOSE: To describe a clinical case of bilateral biopsy-proven IgG4-related disease confined to the tarsal plate. METHOD: Interventional case report. RESULTS: A 58-year-old woman presented with a tarsal swelling in the lateral part of the upper eyelids, with focal ulceration and mucus. Histology revealed fibrotic inflammation with increased IgG4-positive plasma cells fulfilling the criteria of IgG4-related disease (IgG4-RD). Serum IgG4 levels were increased, and pathological fluorodeoxyglucose uptake at positron emission tomography/CT scanning was restricted to the upper eyelids. After treatment with oral and topical prednisone, the tarsal lesions markedly regressed. CONCLUSIONS: Periorbital IgG4-RD may be confined to the tarsal plate. Treatment with systemic and topical steroids may induce significant regression.

Prenatal Risk Factors for PHACE Syndrome: A Study Using the PHACE Syndrome International Clinical Registry and Genetic Repository.

The cause of PHACE syndrome is unknown. In a study of 218 patients, we examined potential prenatal risk factors for PHACE syndrome. Rates of pre-eclampsia and placenta previa in affected individuals were significantly greater than in the general population. No significant risk factor differences were detected between male and female subjects.

Xeroderma pigmentosum clinical practice guidelines.

Xeroderma pigmentosum (XP) is a genetic photosensitive disorder in which patients are highly susceptibe to skin cancers on the sun-exposed body sites. In Japan, more than half of patients (30% worldwide) with XP show complications of idiopathic progressive, intractable neurological symptoms with poor prognoses. Therefore, this disease does not merely present with dermatological symptoms, such as photosensitivity, pigmentary change and skin cancers, but is "an intractable neurological and dermatological disease". For this reason, in March 2007, the Japanese Ministry of Health, Labor and Welfare added XP to the neurocutaneous syndromes that are subject to government research initiatives for overcoming intractable diseases. XP is one of the extremely serious photosensitive disorders in which patients easily develop multiple skin cancers if they are not completely protected from ultraviolet radiation. XP patients thus need to be strictly shielded from sunlight throughout their lives, and they often experience idiopathic neurodegenerative complications that markedly reduce the quality of life for both the patients and their families. Hospitals in Japan often see cases of XP as severely photosensitive in children, and as advanced pigmentary disorders of the sun-exposed area with multiple skin cancers in adults (aged in their 20-40s), making XP an important disease to differentiate in everyday clinical practice. It was thus decided that there was a strong need for clinical practice guidelines dedicated to XP. This process led to the creation of new clinical practice guidelines for XP.

Encephalocraniocutaneous Lipomatosis Without Ocular Malformations.

BACKGROUND: Encephalocraniocutaneous lipomatosis is a rare congenital neurocutaneous syndrome resulting from ectomesodermal dysgenesis and characterized by unique hairless scalp lesions in the form of nevus psiloliparus, ipsilateral ocular malformations, and central nervous system anomalies. According to the 2009 diagnostic criteria proposed by Moog et al., ocular abnormalities are supposed to be the most consistent feature of encephalocraniocutaneous lipomatosis. PATIENT DESCRIPTION: We describe an 18-year-old girl with most of the central nervous system manifestations of encephalocraniocutaneous lipomatosis, major skin alterations including nevus psiloliparus, but no ocular involvement. CONCLUSION: Our patient suggests more variability in clinical features and a more complex genetic/embryonic etiology of encephalocraniocutaneous lipomatosis.

Mosaic Neurocutaneous Disorders and Their Causes.

Neurocutaneous disorders are a heterogeneous group of conditions (mainly) affecting the skin [with pigmentary/vascular abnormalities and/or cutaneous tumours] and the central and peripheral nervous system [with congenital abnormalities and/or tumours]. In a number of such disorders, the skin abnormalities can assume a mosaic patterning (usually arranged in archetypical patterns). Alternating segments of affected and unaffected skin or segmentally arranged patterns of abnormal skin often mirror similar phenomena occurring in extra-cutaneous organs/tissues [eg, eye, bone, heart/vessels, lung, kidney and gut]. In some neurocutaneous syndromes the abnormal mosaic patterning involve mainly the skin and the nervous system configuring a (true) mosaic neurocutaneous disorder; or an ordinary trait of a neurocutaneous disorder is sometimes superimposed by a pronounced linear or otherwise segmental involvement; or, lastly, a neurocutaneous disorder can occur solely in a mosaic pattern. Recently, the molecular genetic and cellular bases of an increasing number of neurocutaneous disorders have been unravelled, shedding light on the interplays between common intra- and extra-neuronal signalling pathways encompassing receptor-protein and protein-to-protein cascades (eg, RAS, MAPK, mTOR, PI3K/AKT and GNAQ pathways), which are often responsible of the mosaic distribution of cutaneous and extra-cutaneous features. In this article we will focus on the well known, and less defined mosaic neurocutaneous phenotypes and their related molecular/genetic bases, including the mosaic neurofibromatoses and their related forms (ie, spinal neurofibromatosis and schwannomatosis); Legius syndrome; segmental arrangements in tuberous sclerosis; Sturge-Weber and Klippel-Trenaunay syndromes; microcephaly/megalencephaly-capillary malformation; blue rubber bleb nevus syndrome; Wyburn-Mason syndrome; mixed vascular nevus syndrome; PHACE syndrome; Incontinentia pigmenti; pigmentary mosaicism of the Ito type; neurocutaneous melanosis; cutis tricolor; speckled lentiginous syndrome; epidermal nevus syndromes; Becker's nevus syndrome; phacomatosis pigmentovascularis and pigmentokeratotica; Proteus syndrome; and encephalocraniocutaneous lipomatosis.

Common Neurocutaneous Syndromes.

Neurocutaneous syndromes are a diverse group of neurologic disorders with concurrent skin manifestations. Most neurocutaneous syndromes have a genetic basis and are believed to arise from a defect in the differentiation of the primitive ectoderm. In this regard, the skin can be a window into the central nervous system and can aid in the diagnosis of neurologic disease in children. The cutaneous signs may be subtle, which places great importance on the physical examination skills of clinicians providing primary care to children. Early recognition can help with proper diagnosis, formulating a treatment plan, anticipating potential complications, making appropriate referrals, and offering genetic counseling to families.

A case of neurocutaneous melanosis and neuroimaging findings.

Neurocutaneous melanosis is a rare congenital disorder which presents with congenital cutaneous nevi and involvement of the central nervous system. We herein present a rare case of a 2-year-old girl who had central nervous system melanosis and giant congenital melanocytic nevi. Magnetic resonance imaging, especially precontrast T1 images play a crucial role in making the diagnosis combined with the skin findings of physical examination.

[Dermato-neuro syndrome during scleromyxedema: efficacy of plasmapheresis and intravenous immunoglobulin]. / Dermatoneuro syndrome au cours d'un scléromyxœdème: efficacité des plasmaphérèses et des immunoglobulines intraveineuses.

BACKGROUND: Dermato-neuro syndrome is a specific neurological complication of scleromyxedema presenting with fever, coma, seizures and flu-like syndrome. To our knowledge, it has only been reported about twenty times in the literature. Its outcome is uncertain. We describe the case of a patient in whom a favorable outcome was achieved using a combination of plasmapheresis and intravenous immunoglobulin (IVIG). PATIENTS AND METHODS: A 57-year-old woman was diagnosed 14 years ago with scleromyxedema resistant to multiple lines of treatment. In November 2011, she presented an initial episode of epileptic seizure followed by post-seizure coma, and later, confusional state with visual hallucinations. She recovered spontaneously within a few days. CT scan, MRI, EEG and screening for infection were perfectly normal, resulting in suspicion of neurological involvement associated with her scleromyxedema. In December 2012 and August 2013, she presented two further episodes of status epilepticus, followed once more by a confusional state, with etiological explorations again proving unfruitful. On this occasion, her confusional state persisted for two months until the initiation of plasmapheresis and IVIG. This combination therapy led to rapid regression of all neurological symptoms and an improvement in her general condition. DISCUSSION: The dermato-neuro syndrome is a rare neurological complication of scleromyxedema. Its pathophysiology is unknown. The monoclonal gammopathy induced by the scleromyxedema could account for the patient's hypercoagulable state and for the formation of neutrophilic aggregates leading to impaired microcirculation. Treatment is empirical and poorly codified. The course of the disease is unpredictable and may be lethal.

Clinical characteristics and risks of large congenital melanocytic naevi: a review of 31 patients at the Sydney Children's Hospital.

Large congenital melanocytic naevi (LCMN) are associated with an increased risk of malignancy and neurocutaneous melanocytosis (NCM). This Australian study aims to assess both the clinical characteristics of LCMN and the risks associated with it. The authors reviewed medical records of the Sydney Children's Hospital Dermatology Outpatient Clinic for the past 10 years and identified 31 eligible patients. A total of 14 boys and 17 girls with a median age of 0.13 years were assessed; 18 lesions were on the trunk, five were on the head, five were on the lower limbs and three were on the upper limbs. In all 20 patients had satellite naevi (the median number of the satellite naevi was 7.5). The patients were followed up for a median duration of 12 months. Central nervous system magnetic resonance imaging was performed on 19 patients and two (6.5%) were found to have NCM. Biopsies were performed on five patients; one patient (3.2%) was found to have benign proliferative nodules of undifferentiated spindle cells but no patient (0%) was found to have a malignancy. The clinical characteristics for the two patients with NCM and the patient with benign proliferative nodules suggest that the risk of both NCM and benign proliferative nodules may be greater with an increased number of satellite naevi and with the LCMN being larger in size.

Gómez-López-Hernández syndrome: another consideration in corneal neurotrophic ulcers.

PURPOSE: To report a case of a Gómez-López-Hernández syndrome (GLHS) variant with corneal neurotrophic ulcer. METHODS: Case report and review of the literature. RESULTS: A 6-year-old child presented with watering in the right eye for 3 days without ocular inflammation or pain. He had a peculiar facial phenotype and scalp alopecia in the right side. Slit-lamp examination showed an epithelial defect in the right eye and a corneal scar around the defect. Belmonte noncontact esthesiometry showed reduced corneal mechanosensory and thermal sensitivity. In vivo confocal microscopy revealed the absence of innervation in the right cornea. There was also an evident insensitivity in the alopecic region. Despite normal magnetic resonance imaging, the phenotypic manifestations along with ocular features suggested the diagnosis of a GLHS variant. CONCLUSIONS: Patients with GLHS remain asymptomatic even when they develop a corneal ulcer. Parents should be advised regarding the susceptibility of an affected child to the development of corneal lesions and the importance of regular follow-up and prompt treatment to prevent vision-threatening abnormalities.

The risk of melanoma and neurocutaneous melanosis associated with congenital melanocytic nevi.

Congenital melanocytic nevi are commonly encountered in clinical practice. Although the development of malignant melanoma arising in small and intermediate congenital melanocytic nevi is rare, there is a significant risk of malignant degeneration associated with large congenital melanocytic nevi, in particular those that arise on the torso in the so-called "bathing trunk" distribution, where the risk is estimated to be about 2.5% to 5%. The risk of malignant melanoma arising within a large congenital melanocytic nevus is highest in the first 5 to 10 years of life and carries a significant mortality. Large congenital melanocytic nevi, in particular those overlying the posterior axis and occurring in the context of multiple satellite melanocytic nevi, are also associated with the development of neurocutaneous melanosis, which may result in neurologic and neurodevelopmental sequelae and is associated with a significant risk of primary central nervous system melanoma and death.

Congenital melanocytic nevi-when to worry and how to treat: Facts and controversies.

Congenital melanocytic nevi (CMN) are evident in 1% to 6% of neonates. In some studies, nevi with clinical, dermatoscopic, and histologic features identical to CMN have had a prevalence of more than 15% in older children and adults, possibly reflecting the "tardive" appearance of nevi programmed from birth. There is ongoing debate about the magnitude of the risk of melanoma and other complications associated with CMN of various sizes and the best approach to management of these lesions. We review the natural history of CMN, including proliferative nodules and erosions during infancy, neurotization, and spontaneous regression, and features of variants such as speckled lentiginous and congenital blue nevi. The risk of melanoma arising within small-sized (<1.5 cm) and medium-sized CMN is low (likely <1% over a lifetime) and virtually nonexistent before puberty. Recent data suggest that melanoma (cutaneous or extracutaneous) develops in approximately 5% of patients with a large (>20 cm) CMN, with about half of this risk in the first few years of life. Melanoma and neurocutaneous melanocytosis (NCM) are most likely in patients with CMN that have a final size of >40 cm in diameter, numerous satellite nevi, and a truncal location. One-third of individuals with NCM have multiple medium-sized (but no large) CMN. In patients at risk for NCM, a screening gadolinium-enhanced magnetic resonance imaging, preferably before age 6 months, and longitudinal neurologic assessment are recommended. Management of CMN depends on such factors as the ease of monitoring (more difficult for large, dark, thick nevi) and cosmetic and psychologic benefits of excision or other procedures. CMN require lifelong follow-up. Periodic total body skin examinations are necessary for all patients with large CMN, even when complete resection (often impossible) has been attempted.