Topical trametinib for epidermal and sebaceous nevi in a child with Schimmelpenning-Feuerstein-Mims syndrome.

We present the case of a 20-month-old girl with Schimmelpenning-Feuerstein-Mims (SFM) syndrome with extensive head, neck, and torso skin involvement successfully managed with topical trametinib. Trametinib interferes downstream of KRAS and HRAS in the MAPK signaling pathway, of which KRAS was implicated in our child's pathogenic variant. Although other dermatologic conditions have shown benefit from oral trametinib, its topical use has not been well reported. Our patient showed benefit from the use of twice-daily topical trametinib, applied to the epidermal and sebaceous nevi over a 16-month period, leading to decreased pruritus and thinning of the plaques.

A human patient-derived cellular model of Joubert syndrome reveals ciliary defects which can be rescued with targeted therapies.

Joubert syndrome (JBTS) is the archetypal ciliopathy caused by mutation of genes encoding ciliary proteins leading to multi-system phenotypes, including a cerebello-retinal-renal syndrome. JBTS is genetically heterogeneous, however mutations in CEP290 are a common underlying cause. The renal manifestation of JBTS is a juvenile-onset cystic kidney disease, known as nephronophthisis, typically progressing to end-stage renal failure within the first two decades of life, thus providing a potential window for therapeutic intervention. In order to increase understanding of JBTS and its associated kidney disease and to explore potential treatments, we conducted a comprehensive analysis of primary renal epithelial cells directly isolated from patient urine (human urine-derived renal epithelial cells, hURECs). We demonstrate that hURECs from a JBTS patient with renal disease have elongated and disorganized primary cilia and that this ciliary phenotype is specifically associated with an absence of CEP290 protein. Treatment with the Sonic hedgehog (Shh) pathway agonist purmorphamine or cyclin-dependent kinase inhibition (using roscovitine and siRNA directed towards cyclin-dependent kinase 5) ameliorated the cilia phenotype. In addition, purmorphamine treatment was shown to reduce cyclin-dependent kinase 5 in patient cells, suggesting a convergence of these signalling pathways. To our knowledge, this is the most extensive analysis of primary renal epithelial cells from JBTS patients to date. It demonstrates the feasibility and power of this approach to directly assess the consequences of patient-specific mutations in a physiologically relevant context and a previously unrecognized convergence of Shh agonism and cyclin-dependent kinase inhibition as potential therapeutic targets.

Laminin-521 Protein Therapy for Glomerular Basement Membrane and Podocyte Abnormalities in a Model of Pierson Syndrome.

Background Laminin α5ß2γ1 (LM-521) is a major component of the GBM. Mutations in LAMB2 that prevent LM-521 synthesis and/or secretion cause Pierson syndrome, a rare congenital nephrotic syndrome with diffuse mesangial sclerosis and ocular and neurologic defects. Because the GBM is uniquely accessible to plasma, which permeates endothelial cell fenestrae, we hypothesized that intravenous delivery of LM-521 could replace the missing LM-521 in the GBM of Lamb2 mutant mice and restore glomerular permselectivity.Methods We injected human LM-521 (hLM-521), a macromolecule of approximately 800 kD, into the retro-orbital sinus of Lamb2-/- pups daily. Deposition of hLM-521 into the GBM was investigated by fluorescence microscopy. We assayed the effects of hLM-521 on glomerular permselectivity by urinalysis and the effects on podocytes by desmin immunostaining and ultrastructural analysis of podocyte architecture.Results Injected hLM-521 rapidly and stably accumulated in the GBM of all glomeruli. Super-resolution imaging showed that hLM-521 accumulated in the correct orientation in the GBM, primarily on the endothelial aspect. Treatment with hLM-521 greatly reduced the expression of the podocyte injury marker desmin and attenuated the foot process effacement observed in untreated pups. Moreover, treatment with hLM-521 delayed the onset of proteinuria but did not prevent nephrotic syndrome, perhaps due to its absence from the podocyte aspect of the GBM.Conclusions These studies show that GBM composition and function can be altered in vivovia vascular delivery of even very large proteins, which may advance therapeutic options for patients with abnormal GBM composition, whether genetic or acquired.

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

BACKGROUND: 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. OBJECTIVES: To provide unified guidelines for the treatment of IH with propranolol. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

PHACE syndrome--clinical features, aetiology and management.

UNLABELLED: PHACE syndrome comprises a spectrum of anomalies including posterior fossa malformations, haemangioma, arterial anomalies, cardiac defects and eye anomalies. PHACE should be considered in any patient with a large facial segmental infantile haemangioma (IH), and multidisciplinary management is crucial. Low-dose propranolol is effectively for the treatment of IH associated with PHACE syndrome. Recent evidence suggests IH is comprised of mesoderm-derived haemogenic endothelium. CONCLUSION: The embryonic developmental anomaly nature of IH provides an insight into the origin of PHACE syndrome.

Orbital Hemangioma with Intracranial Vascular Anomalies and Hemangiomas: A New Presentation of PHACE Syndrome?

We present two cases of infants with a similar constellation of clinical findings: retro-orbital infantile hemangioma (IH), internal carotid artery (ICA) arteriopathy, and intracranial IH. In both cases, intracranial vascular anomalies and hemangiomas were found incidentally during evaluation of unilateral proptosis. Neither infant had evidence of cutaneous segmental IH of the face or neck, which might have provided a clue to the diagnosis of PHACE syndrome or of intracranial hemangiomas. In one case, intracranial involvement was particularly extensive and function threatening, with mass effect on the brain parenchyma. These cases serve to highlight the fact that clinical findings of proptosis, globe deviation, and strabismus should prompt immediate imaging to confirm the presence of orbital IHs and to exclude other diagnoses. Moreover, based on our cases and the embryologic origin of the orbit as a unique developmental unit, patients with confirmed retro-orbital IHs should undergo evaluation for anomalies associated with PHACE syndrome. Patients with orbital IHs and an additional major criterion for PHACE syndrome should be considered to have definite, and not just possible, PHACE syndrome.

Growth hormone replacement in patients with PHACE association and hypopituitarism.

Partially empty sella with growth hormone (GH) deficiency is rarely reported in association with PHACE (posterior fossa anomalies, cervicofacial infantile hemangiomas [IHs], arterial anomalies, cardiac defects, eye anomalies, and midline/ventral defects). Consequently, little is known about the effect of GH replacement on the proliferation and involution of IHs in children with PHACE. We describe two children with PHACE and partially empty sella, both of whom received GH replacement for treatment of hypopituitarism. In our first patient we observed erythema and prominence of the vasculature in the hemangioma shortly after initiation of therapy at age 20 months, although after 4 weeks of treatment the appearance of the hemangioma stabilized and little change was seen during eight additional years of therapy. In our second patient we noted enlargement of the hemangioma after starting low-dose GH at age 5 years, prompting discontinuation of GH replacement after 3 months of therapy. The hemangiomas continued to grow after discontinuation of GH treatment. GH administration in our patients was associated with erythema and prominence of IHs. Our findings suggest that GH replacement therapy may promote transient or more prolonged proliferation of IHs and should be administered with close clinical monitoring.

PHACE syndrome: a retrospective review of 23 patients.

We present 23 patients with PHACE syndrome showing similarities in our population with data that already exist while highlighting neurodevelopmental occurrences arising in a subset of these patients.

A review of preclinical evidence of Cryptolepis nigrescens (Wennberg) L. Joubert. and Bruyns., Prosopsis africana (Guill. and Perr.) Taub. and Pterygota macrocarpa K. Schum. traditionally used to manage tumours in Ghana.

ETHNOPHARMACOLOGICAL RELEVANCE: Cancer stands as one of the leading causes of death worldwide according to the World Health Organization (WHO), and it has led to approximately 10 million fatalities in 2020. Medicinal plants are still widely used and accepted form of treatment for most diseases including cancer in Ghana. This review presented Cryptolepis nigrescens (Wennberg) L. Joubert. and Bruyns., Prosopsis africana (Guill. and Perr.) Taub. and Pterygota macrocarpa K. Schum. as medicinal plants that are traditionally used to treat tumour growth, amongst other diseases, in the Ashanti region of Ghana. AIM OF REVIEW: This paper aims to present a comprehensive review on the botanical description, ecological distribution, ethnomedicinal uses, phytochemical composition and ethnopharmacological relevance of C. nigrescens, P. africana and P. macrocarpa. MATERIALS AND METHODS: The review covers works published between 1962 and 2023 from various countries. Published books, thesis, scientific and medical articles on C. nigrescens, P. africana and P. macrocarpa were collected from the following databases: 'Scopus', 'Science Direct', 'Medline', 'PubMed', 'Research Gate' 'Google Scholar, and 'Springer link' using the keywords. RESULTS: Phytochemical analysis of C. nigrescens, P. africana and P. macrocarpa revealed the presence of some prominent bioactive compounds such as convallatoxin, 7,3,4-trihydroxy-3-methoxyflavanone and dioxane, respectively. Plant extracts and isolated compounds of these medicinal plants exhibited a wide range of ethnopharmacological activities including antimicrobial, anti-inflammatory, antioxidant, analgesic, cytotoxic, antimalarial, antipyretic, haematinic, hepato-protective, aphrodisiac and antihypertensive properties. CONCLUSION: The present review on C. nigrescens , P.africana and P. macrocarpa provided a credible summary of the ethnopharmacological research conducted on these medicinal plants till date. The data also highligted the potential therapeutic profiles of these plants in Ghana that could serve as foundation for future studies. Additionally, the information significantly supported the traditional and commercial use of these plants among the people.

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.

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.

Nonsurgical management of epiblepharon using hyaluronic acid gel.

A 4-month-old infant with epiblepharon of the right lower eyelid presented with medial eyelashes touching the corneal surface in primary gaze and resultant punctate epithelial keratopathy. Hyaluronic acid gel (Juvederm Ultra) 0.2 ml was injected in the suborbicular plane in the valley above the abnormal skin fold. Immediate out-turning of the eyelid margin was obtained, which persisted at 1-week, 1-month, and 4.5-month follow-up visits with no lash-corneal touch even in down gaze. Epiblepharon, which often self corrects with increasing age, can be effectively corrected with this minimally invasive nonsurgical option when it is symptomatic, and is a threat to the corneal health.

Utilisation of advanced MRI techniques to understand neurovascular complications of PHACE syndrome: a case of arterial stenosis and dissection.

PHACE syndrome is a rare disorder with posterior fossa brain malformations, segmental infantile haemangiomas, arterial anomalies, cardiac defects and eye anomalies. Cerebral and cervical arterial abnormalities occur commonly in these patients, predisposing subjects with PHACE syndrome to neurovascular complications including migraine-like headaches, moyamoya vasculopathy, arterial dissection and arterial ischaemia stroke. We leveraged institutional MRI protocols developed for adult neurovascular disease to better elucidate the pathogenesis of the arterial alternations observed in PHACE. Using high-resolution vessel wall and 4D flow MRI, we demonstrated enhancement, focal dissection and altered blood flow in a 7-year-old girl with PHACE syndrome. This is the first-time vessel wall imaging has been used to detail the known arterial changes in PHACE, and these findings may indicate that progressive vascular narrowing and vessel wall changes/inflammation are a factor in chronic headaches and other arterial complications seen in subjects with PHACE syndrome.

Changes in Ocular Blood Flow after Ranibizumab Intravitreal Injection for Diabetic Macular Edema Measured Using Laser Speckle Flowgraphy.

PURPOSE: To evaluate the effects of intravitreal ranibizumab (IVR) treatment on the blood flow of the optic nerve head (ONH) and of retinal vessels of the peripapillary region of eyes with diabetic macular edema (DME) assessed using laser speckle flowgraphy (LSFG). METHODS: Forty eyes of 30 patients treated with IVR for DME were included in this prospective clinical study. Mean blur rate (MBR) and relative flow volume (RFV) of the ONH and of a superior retinal artery and an inferior retinal vein of the peripapillary region were measured using LSFG at baseline, 2 weeks (T1), and 1 month (T2) after IVR injection. In addition, best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were measured in all cases. RESULTS: The BCVA improved and CRT decreased significantly during the follow-up period (p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA, p < 0.010). MBR-related parameters of the ONH such as MBR of all area (MA), MBR of vascular area (MV), and MBR of tissue area (MT) decreased significantly at 2 weeks after IVR compared to baseline values (MA. CONCLUSION: IVR injection leads to a reduction of ocular blood flow both in the ONH and in the retinal peripapillary vessels associated with peripapillary vessel constriction. The reduction of CRT and related improvement of vision may be related to the changes in ocular blood flow.

Nonsurgical management of congenital eyelid malpositions using hyaluronic Acid gel.

PURPOSE: To report our preliminary experience using hyaluronic acid gel fillers as a nonsurgical alternative in the management of congenital eyelid malpositions. METHODS: In this retrospective interventional case series, 5 patients (10 eyes) with congenital eyelid malpositions, including eyelid retraction, ectropion, euryblepharon, epiblepharon, and abnormalities associated with a shallow orbit, with resultant lagophthalmos and/or keratopathy and tearing were evaluated before and after injection with hyaluronic acid gel (Restylane) in the pretarsal and/or septal regions of the affected eyelid(s). Pretreatment, posttreatment, and follow-up photographs were analyzed for eyelid position and degree of eyelid closure and lagophthalmos, and slit-lamp evaluation of the degree of keratopathy. RESULTS: All 5 patients demonstrated significant improvement of eyelid position and degree of keratopathy. The mean improvement in lagophthalmos was 4.5 mm (range, 2-7 mm). The average volume of hyaluronic acid gel used was 0.5 ml per eyelid. Complications were minor, including transient edema and ecchymosis at the sites of injection. Of the 10 eyelids injected, only one had increased astigmatism after injection. CONCLUSIONS: Hyaluronic acid gel shows promise as a safe and effective nonsurgical treatment for the management of certain eyelid malpositions, disorders traditionally requiring surgical intervention if aggressive ocular lubrication fails. This treatment is particularly useful in such patients who are commonly premature with poor general health and serves as a temporizing measure by allowing the much needed tissue expansion to take effect over time.

Joubert syndrome with multiple pituitary hormone deficiency.

Joubert syndrome (JS) and JS-related disorders are a group of developmental delay, multiple congenital anomalies and complex midbrain-hindbrain malformations. A few cases of JS with multiple pituitary hormone deficiency (MPHD) have been reported in literature. Here, we presented an unusual presentation of JS in a newborn with MPHD. This case is intended to draw attention to the rare association of JS and MDPH by increasing the awareness of this syndrome.

Preoperative administration of propranolol reduced the surgical risks of PHACES syndrome in a 14-month-old girl.

PHACES syndrome is an uncommon neurocutaneous disorder first identified in 1996. Patients with PHACES syndrome often require surgical treatment for their anomalies, including intracranial vasculopathy, coarctation/interruption of the aorta, intracardiac defects, glaucoma/cataract and sternal defects. Risk factors associated with the symptoms of intraoperative/perioperative management include ischaemic stroke due to the cerebral vasculopathy, airway obstruction due to the subglottic/tracheal haemangiomas and massive bleeding due to the large haemangiomas. Recently, propranolol is considered as first-line therapy for patients with infantile haemangiomas (IHs). However, until now, there have been no reported cases of PHACES syndrome treated by propranolol to reduce the surgical risks associated with IH. In this report, we describe a case of a 14-month-old Japanese girl with PHACES syndrome treated by propranolol for IH before surgical closure of the ventricular septum defect. Oral administration of propranolol was effective in decreasing the size of IH, leading to the uneventful perioperative course.