Topics on Continuous Training

V. Cantarín Extremera, A. Duat Rodríguez

Consultant physicians. Neuropediatrics Section. Niño Jesús University Children’s Hospital. Madrid

Abstract Neurocutaneous syndromes represent an heterogeneous group of genetic disorders characterized by simultaneous involvement of the central nervous system and the skin. Among the most relevant in the pediatric population are Neurofibromatosis type 1 (NF1), Tuberous Sclerosis Complex (TSC), Sturge-Weber Syndrome (SWS), and Incontinentia Pigmenti (IP). NF1, associated with pathogenic variants in NF1 gene, is characterized by café-au-lait macules, neurofibromas, and an increased risk of optic pathway glioma. TSC, resulting from mutations in TSC1 or TSC2 genes, presents with various types of skin lesions such as hypomelanotic macules and facial angiofibromas, along with cerebral, renal, ophthalmologic, and cardiac involvement, in addition to epilepsy and neurodevelopmental disorders. SWS is caused by somatic mutations in GNAQ gene and manifests with the characteristic port-wine stain, leptomeningeal angiomatosis, and glaucoma. IP, an X-linked condition caused by mutations in IKBKG, predominantly affects females and presents with stage-specific cutaneous lesions as well as potential neurological and ocular involvement. Early clinical recognition, often initiated through dermatological findings by the pediatrician, is crucial for timely diagnosis and intervention. Targeted therapies, such as mTOR or MEK inhibitors, are available for selected cases.

 

Resumen Los síndromes neurocutáneos constituyen un grupo heterogéneo de enfermedades genéticas caracterizadas por la afectación simultánea del sistema nervioso central y la piel. Entre los más destacables en la población pediátrica se encuentran: la neurofibromatosis tipo 1 (NF1), el complejo de esclerosis tuberosa (CET), el síndrome de Sturge-Weber (SSW) y la incontinencia pigmentaria (IP). La NF1, asociada a variantes patogénicas en el gen NF1, se caracteriza por manchas “café con leche”, neurofibromas y un riesgo incrementado de glioma del nervio óptico. El CET, consecuencia de mutaciones en TSC1 o TSC2, presenta diferentes tipos de lesiones cutáneas, como máculas hipomelanóticas o angiofibromas, lesiones cerebrales, renales, oftalmológicas y cardiacas, además de epilepsia y trastornos del neurodesarrollo. El SSW se debe a mutaciones somáticas en GNAQ y se manifiesta con la típica mancha en vino de Oporto, angiomatosis leptomeníngea y glaucoma. La IP, enfermedad ligada al cromosoma X, por mutaciones en IKBKG, afecta predominantemente a mujeres y presenta lesiones cutáneas evolutivas junto con posible compromiso neurológico y oftalmológico. El reconocimiento clínico precoz, frecuentemente a partir de hallazgos dermatológicos, por parte del pediatra, es fundamental para el diagnóstico e intervención oportunos. Existen terapias dirigidas, como los inhibidores de mTOR o MEK en casos seleccionados.

 

Key words: Neurocutaneous syndromes; Neurofibromatosis type 1; Tuberous sclerosis complex; Sturge-Weber syndrome; Incontinentia pigmenti.

Palabras clave: Síndromes neurocutáneos; Neurofibromatosis tipo 1; Esclerosis tuberosa; Síndrome de Sturge-Weber; Incontinencia pigmentaria.

 

 

Pediatr Integral 2025; XXIX (6): 450 – 461

 

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Neurocutaneous syndromes

https://doi.org/10.63149/j.pedint.72

 

Introduction

Neurocutaneous disorders are multisystem diseases primarily characterized by involvement of the central nervous system and the skin. They may present various inheritance patterns or appear sporadically, with progressive manifestations and diverse phenotypes. Early clinical recognition, especially through skin examination, is essential to guide treatment.

Neurocutaneous disorders are a group of genetic diseases that predominantly affect the central nervous system and the skin, due to their common origin in the primitive ectodermal tissue. It should be noted that symptoms and signs usually appear progressively from birth to adulthood, with variable phenotypic expression even within the same family, posing a diagnostic challenge. Pediatricians should be familiar with the most common neurocutaneous disorders, since a simple skin examination can lead to the differential diagnosis and to better patient care. Treatment is usually symptomatic, although advances in the understanding of pathophysiology have led to the development of specific therapies for many of the complications they present(1,2).

More than fifty neurocutaneous syndromes are known to date, but this article will focus on the most common ones in pediatrics.

Neurofibromatosis type 1

Introduction

Neurofibromatosis type 1 is a multisystem disease characterized by café-au-lait spots (CALS), neurofibromas, and an increased risk of tumor development. The morbidity and mortality are associated with the multisystem complications that may occur throughout its course.

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome, affecting 1 in every 3,000 to 4,000 live births. The responsible gene (NF1) is located on chromosome 17q11.2 and is altered by de novo mutations in 50% of cases; the remainder are inherited in an autosomal dominant manner. NF1 is a tumor suppressor gene that synthesizes a protein called neurofibromin, which helps regulate the cell cycle by inhibiting the RAS/MAPK (mitogen-activated protein kinase pathway) and PI3K-AKT-mTOR (phosphatidylinositol 3-kinase–Akt signaling–mammalian target of rapamycin pathway) signaling pathways. When these pathways are uncontrolled, the risk of tumor formation increases, as occurs in patients with NF1(2).

Clinical manifestations

The clinical manifestations of NF1 are extremely variable, depending on both the individual and the age (Fig. 1) and include: CALS, axillary and inguinal freckles, peripheral neurofibromas, and Lisch nodules. Severe complications affect a minority of patients; however, they are what determine the morbidity and mortality of this disease(3).

Among the clinical manifestations, the following should be underscored:

 

• Rasopathy phenotype: macrocephaly, short stature, subtle facial features (hypertelorism with antimongoloid palpebral fissures, epicanthus, ptosis and posteriorly rotated ears with thickened helix) and thoracic abnormalities (pectus carinatum and excavatum)(3).

• Skin manifestations: typical ones include: CALS (100%) (number ≥ 6); freckles, which are small CALS located in axillary and inguinal folds (Fig. 2); anemic nevi (50%), pale macules with a very subtle polylobulated contour, generally in the presternal region, which become evident when the area is lightly rubbed; and juvenile xanthogranulomas, which consist of a solitary or multiple orange papule, anywhere on the body(3,4).

• Skeletal manifestations: dysplasia of long bones stand out, affecting the sphenoid, vertebral and pseudoarthrosis, which can cause deformities. They frequently suffer from scoliosis, mainly cervical or upper thoracic(3,4).

• Ocular manifestations: Lisch nodules of pigmented and asymptomatic hamartomas of the iris, which increase in number and size with age(3,4).

• Neurological manifestations: learning disorders and attention deficit hyperactivity disorder (ADHD) are the major developmental problems in children with NF1. At the central nervous system (CNS) level, Arnold Chiari malformation type I, hydrocephalus, cerebrovascular lesions (stenosis, aneurysms or moyamoya syndrome) and hypersignal characteristics in T2 sequences of cranial magnetic resonance imaging (MRI) or UBOs (unidentified bright objects) are described, corresponding to areas of intramyelinated vacuolization, not associated with clinical alterations(3,4).

• Neurofibromas: these are the most common tumors in NF1 and can occur in any location. Although benign, depending on size and location, they can cause complications such as pain and deformities. Sometimes, they are palpated rather than seen. Some, histologically, correspond to plexiform neurofibromas, which will be relevant for treatment. Malignant transformation of a neurofibroma into a neurofibrosarcoma is rare in childhood, but warning signs include: sudden increase in size, change in texture (increased consistency), severe pain, and unusual neurological symptoms(3).

• Optic pathway gliomas (OPG): most common CNS tumor, affecting up to 30% of children with NF1. Most are asymptomatic with a stable course, but 7-17% may produce symptoms (unilateral or bilateral decreased visual acuity, proptosis, strabismus, nystagmus, etc.)(3).

• Others: growth disorders, puberty, osteoporosis or alterations in the cardiovascular system, mainly fibromuscular arterial dysplasia. Arterial hypertension may be of idiopathic cause, due to a pheochromocytoma, or secondary to a renal or aortic vasculopathy(3).

Diagnosis

The diagnosis of NF1 is established through a series of clinical criteria. Some early manifestations in young children, although not included in the diagnostic criteria, can be highly suggestive of NF1.

The US National Institutes of Health defined a consensus of clinical criteria for the diagnosis of NF1 in 1988, updated in 2021(5) (Table I). In infants and young children, we should look for other manifestations, such as congenital superficial plexiform neurofibromas, anemic nevi, juvenile xanthogranuloma, or the presence of a rasopathy phenotype. Molecular confirmation can lead to the diagnosis in up to 95%.

 

Differential diagnosis

The differential diagnosis of NF1 is established with other diseases that present CALS, tumors or other rasopathies.

In addition to considering other pigmentary conditions, diseases that present CALS or diseases that cause tumors, in childhood other rasopathies must be contemplated, mainly Legius syndrome, characterized by CALS and ephelides, without neurofibromas or optic gliomas(3).

Treatment

Patients with NF1 require comprehensive care to detect everything from learning disabilities and ADHD to symptoms arising from tumor manifestations that require other pharmacological or surgical interventions(6). Selumetinib, a MEK inhibitor, is approved for use in children older than 2 years of age with symptomatic, inoperable plexiform neurofibromas, the main symptoms being pain and tumor growth(3).

Tuberous sclerosis complex

Tuberous sclerosis complex (TSC) is a neurocutaneous disorder characterized by benign tumors in the brain, heart, kidney, and eye, as well as various skin lesions (hypopigmented macules and facial angiofibromas, among others). Epilepsy and neurodevelopmental disorders are the main morbidities in children.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder characterized by a predisposition to the formation of benign tumors (hamartomas) in multiple organs. The mutations identified in TSC are located in two genes: TSC1 (9q34.13) and TSC2 (16p13.3), which encode the proteins hamartin and tuberin, respectively, which form a complex that regulates cell growth through the mTOR pathway. Any mutation in TSC1 or TSC2 will result in uncoordinated activation of mTOR, leading to the development of tumors. A mutation in TSC1 and TSC2 is evident in 90% of cases, leaving 10% without a known mutation, which may be due to mosaicism. There is no relationship between genotype and phenotype, although mutations in TSC2 have been linked to greater severity due to neurological involvement(7).

Clinical manifestations

Skin lesions, present in 95-100% of patients with TSC, primarily hypopigmented macules, are a key diagnostic marker of the disease, even at birth. Cardiac rhabdomyomas, renal angiomyolipomas, and cortical tubers are the key findings of this entity(8).

Skin/mucous membrane/dental lesions

• Hypopigmented stains. Flat, white lesions, typically described as “ash leaf” shaped, but variable. Hypomelanosis of the hair (poliosis or white patch) is also considered a hypopigmented macule(7,9).

• Confetti lesions. Hypopigmented macules, between 1-3 mm, dispersed over a body region such as the legs or arms(7,9).

• Facial angiofibromas. These are papular lesions with a malar or perioral distribution and can be confused with acne in adolescence(7,9).

• Fibrous cephalic plates. Raised lesions on the face or scalp with a color similar to healthy skin, pink, red, or even brown(7,9).

• Shagreen patches (Fig. 3). They are relatively specific of TSC. They present as plaque-like lesions, like “orange peel skin”, usually in the lumbosacral region(7,9).

• Ungual fibromas. Skin-colored or reddish tumors that most often appear on the toes. Sometimes, a groove or canaliculi can be seen in the nail beforehand(7,9).

• Oral fibromas. These are fibrous nodules, usually located in the gums, although they can also be seen on the tongue, lips, and jugal mucosa(7,9).

• Dental enamel stippling.

Neurological manifestations

Epileptic seizures are one of the most prevalent clinical manifestations in TSC (90%), being this the main reason for diagnosis, although almost all patients already have other previous cutaneous stigmata(8). Another important aspect due to their prevalence (50%) are neurodevelopmental disorders, known as neuropsychiatric disorders associated with TSC (TAND)(10).

Among the neuropathological findings of the CNS the following stand out:

• Cortical tubers/dysplasias (Fig. 4). These are focal abnormalities of brain architecture, responsible for the development of epilepsy, not due to the tubers themselves, but rather due to the perituberal tissue(7,9).

• Subependymal nodules (SEN) (Fig. 4). Lesions located in the wall of the ventricles, generally close to the foramen of Monro. They develop during fetal life and degenerate or calcify later(7,9).

• Giant cell astrocytomas, or SEGAs (Fig. 4), are benign, slow-growing tumors that typically lie adjacent to the foramen of Monro and can cause hydrocephalus due to obstruction, with symptoms such as headache, vomiting, and papilledema. They occur in 6–18% of patients with TSC, even congenitally(7,9,11).

Cardiological manifestations

Rhabdomyomas are the most common cardiac tumor in the TSC and can be diagnosed prenatally (second and third trimesters of pregnancy) or during the first year of life. Although they are usually clinically silent and resolve spontaneously, they can cause hemodynamic compromise and rhythm disturbances, such as Wolff-Parkinson-White syndrome(8,9).

Ophthalmological manifestations

Eye injuries associated with TSC rarely affect vision.

• Retinal hamartomas. These are flat, often light gray or yellow lesions with blurred edges that are visible on the retina(7,9).

• Retinal achromatic patches. Lesions of retinal hypopigmentation(9).

Nephrological manifestations

Responsible for significant morbidity and mortality, mainly in the adult population.

• Renal angiomyolipomas (AMLs). These are benign tumors that, although often asymptomatic, can cause kidney failure, flank pain, hematuria, and spontaneous hemorrhage, which can be life-threatening(7,9).

• Renal cysts. They can range from microscopic to a renal polycystic syndrome phenotype associated with contiguous genes TSC2/PKD1. They have been linked to altered kidney function(9).

Pulmonary manifestations

• Lymphangioleiomyomatosis (LAM). It affects up to 80% of adult women with TSC, although cases have been described in the pediatric population, hence the importance of asking about exercise intolerance or dyspnea(9,12).

Other manifestations

Aneurysms, mainly at the aortic and intracranial level(8,13), non-renal hamartomas in the liver or adrenal glands, bone cysts, rectal polyps and neuroendocrine tumors, mainly located in the pancreas(7).

Diagnosis

The last International Consensus Conference held in 2012(14), with the 2021 update(9), defined the currently valid diagnostic criteria for TSC (Table I). Identification of a pathogenic mutation in TSC1 or TSC2 is enough to make a definitive diagnosis of TSC, although a normal result does not exclude the disease if it meets clinical diagnostic criteria.

Differential diagnosis

When a single patient presents several of the characteristic clinical or radiological criteria, the diagnosis of TSC is straightforward, but the isolated appearance of hypopigmented macules, late angiofibromas, or angiomyolipomas can be seen in other syndromes.

The diagnosis of TSC is usually straightforward when typical signs, such as MRI findings, rhabdomyomas, or hypopigmented macules, are present. However, it becomes more complicated when these manifestations occur in isolation. For example, hypopigmented macules can also be seen in childhood without TSC; late-onset facial angiofibromas could be due to syndromes such as MEN1 or Birt-Hogg-Dubé (skin lesions, lung cysts, and kidney tumors); “confetti” macules in adults may be a sign of sun damage; and other combinations of typical TSC lesions with CALS or angiomyolipomas can also be found in constitutional mismatch repair deficiency syndrome, a genetic disorder with a high predisposition to cancer(7,15).

Treatment

mTOR inhibitors play an important role in managing many of the comorbidities of TSC, such as SEGA, AML, and epilepsy. For the latter, close monitoring and preventive treatment before the onset of seizures can determine a child’s prognosis.

Today, the use of mTOR inhibitors (rapamycin and everolimus) is recognized as first-line treatment for SEGA in children and adults, pulmonary AML and LAM in adults, and epilepsy in children 2 years of age and older. They are also used topically for skin lesions, primarily facial angiofibromas(16).

With regards to epilepsy, electroencephalogram (EEG) monitoring for the appearance of epileptiform abnormalities, preventive treatment with vigabatrin when these abnormalities appear, and early recognition of seizures by caregivers are the most effective measures for reducing the morbidity associated with epilepsy. Likewise, early assessment of the possibility of epilepsy surgery is essential(17).

In the case of SEGA management, in addition to mTOR inhibitors, the participation of an expert neurosurgeon is required due to the possibility of surgical resection(18).

Sturge-Weber syndrome

Introduction

Sturge-Weber syndrome is a neurocutaneous condition characterized by abnormalities in the pathways responsible for angiogenesis, resulting in changes in the skin, eyes, and brain.

Sturge-Weber syndrome (SWS) is another of the most common neurocutaneous diseases, with a frequency of 1 in every 20,000 to 50,000 live births. 80-90% of SWS cases are due to a somatic mutation in GNAQ (c.548G>A; p.Arg183Gln), which encodes a Gαq protein involved in cell signaling. In a small percentage of cases with atypical phenotypes, due to milder neurological involvement, a mutation in GNA11, a homologous gene, has been identified. These alterations lead to increased signaling in pathways such as RAS/MAPK and PI3K/AKT/mTOR, associated with angiogenesis and abnormal vessel growth. The regional distribution of the mutation during embryonic development explains the specific involvement of the brain, skin, and eyes(19,20).

Clinical manifestations

Typical clinical manifestations include facial port-wine stain (PWS), ipsilateral leptomeningeal angioma, and congenital or early-onset glaucoma. Neurological involvement may include refractory epilepsy, hemiparesis, cognitive impairment, and neurobehavioral disorders. Migraine-like headaches and stroke-like episodes are also characteristic.

Skin manifestations

• Port-wine stain (PWS). In a child born with PWS, the risk of developing SWS ranges from 7% to 63%. Extensive hemifacial involvement, at the level of the forehead and upper eyelid, or when it is bilateral, increases the likelihood of SWS. 10% may not have this PWS. Eyelid involvement is often associated with both cerebral involvement and the presence of glaucoma(20,21).

Neurological manifestations

• Leptomeningeal angioma (Fig. 5). A microvascular malformation that extends through the cerebral cortex, causing parenchymal atrophy and calcifications. Brain involvement is bilateral in approximately 15% of cases. There is no correlation between the extent of facial PWS and that of brain involvement; however, the extent of the leptomeningeal angioma is a predictor of the severity of neurological complications(20,21).

 

• Epilepsy. Epilepsy affects 75-100% of patients with SWS, beginning in the first year of life. Treatment may include, in addition to anti-seizure drugs, epilepsy surgery(20,21).

• Episodes that simulate stroke or stroke-like. Episodes likely secondary to abnormal blood flow dynamics, venous stasis, and vasogenic leak. Symptoms include headache, hemiparesis, or visual field disturbance. They may occur spontaneously, following head trauma, fasting, stress, or a seizure. The deficits associated with these events are usually more pronounced and long-lasting than common post-seizure weakness(20,21).

• Headache. It occurs in 30 to 50% of patients with SWS and is related to blood flow disturbances. In adolescents and adults, the headache usually has migraine characteristics, but in children it can be more nonspecific and present as a worsening of the motor deficit. It may be associated with intercurrent seizures and last for several days, becoming very disabling(20,21).

• Disorders of neurodevelopment. Psychomotor delay, cognitive deficit, autism spectrum disorder, ADHD, oppositional defiant disorder, and conduct disorder affect patients with SWS at a higher rate than the general population(20,21).

Ocular manifestations

• Glaucoma. It can appear at birth or during childhood. It is usually ipsilateral to the PWS and brain involvement. It is the main cause of vision loss(20). If it causes symptoms, it consists of excessive tearing, rubbing, sensitivity to light and/or cloudy appearance of the cornea(22).

• Choroidal hemangioma. It is a benign vascular tumor of the posterior segment of the eye and can cause deduced visual acuity, refractive defect, scotoma and retinal detachment(20,22).

Other symptoms

Central hypothyroidism or growth hormone deficiency, as well as sleep apnea, should be monitored in these patients(21).

Diagnosis

Involvement in two of the three main organs (brain, eye or skin) constitutes the diagnosis of this entity, and genetic study is not necessary due to the difficulty of differentiating patients truly affected by SWS from those who only have exclusive cutaneous involvement.

Key diagnostic criteria include two of the following three features: port-wine stain present at birth in the high-risk distribution, vascular malformations of the eye, and brain MRI findings of leptomeningeal angiomatosis. If the newborn is considered at risk for SWS, they should be referred for evaluation by an experienced ophthalmologist and neurologist(21). For neuroimaging, brain MRI with and without gadolinium enhancement is recommended, although the timing is still debated(22). Genetic testing for a mutation in the GNAQ gene is not routinely indicated because the mutation is rarely detected in the blood and, if found, does not distinguish individuals with isolated PWS from true SWS(1).

Differential diagnosis

In the presence of a PWS in a newborn, a differential diagnosis should be made with other skin lesions, such as vascular tumors (infantile hemangioma and congenital hemangioma) and vascular malformations (isolated PWS, nevus simplex/salmon spot, and telangiectasias).

Treatment

Treatment for Sturge-Weber syndrome is symptomatic and multidisciplinary. It includes: epilepsy control with anti-seizure drugs or surgery, glaucoma management with medical or surgical treatment, and laser treatment for port-wine stains. Low-dose aspirin can prevent stroke-like episodes. Although still in research, mTOR inhibitors show promising results.

Treatment is based on the symptoms and signs that are present(20-24):

• PWS: pulsed laser is used to target sclerosis of dilated vessels. Although it is partially effective (whitening only in 10%), requires multiple sessions, is painful and may require photodynamic therapy or topical antiangiogenics as an adjunct.

• Glaucoma: eye drops are used (carbonic anhydrase inhibitors, beta-blockers, prostaglandins or alpha-agonists) and/or surgery (goniotomy, trabeculectomy or valves).

• Epilepsy: there is no anti-seizure drug of choice, although the possibility of epilepsy surgery should be considered. In recent years, prophylactic strategies have been employed with early use of anti-seizure drugs and aspirin (3-5 mg/kg/day).

• Headaches: migraines are managed with pain relievers, hydration, triptans and, for prophylaxis, drugs such as flunarizine, valproic acid, gabapentin or topiramate.

• Stroke-like episodes: aspirin prophylaxis (3-5 mg/kg/day) is recommended to reduce their frequency.

The involvement of the mTOR pathway has opened the debate on the use of inhibitors in the prevention/treatment of SWS-associated morbidities. Further studies are needed to establish a definitive answer(21).

Incontinentia pigmenti

Introduction

Incontinentia pigmenti (IP) is a genetic disease that affects almost exclusively women, with a developmental pattern of primarily cutaneous manifestations, but also findings at the CNS level, skin and appendages due to a mutation in the IKBKG gene.

It is a rare, X-linked dominantly inherited disease affecting females and mostly fatal in males. Approximately 10–25% of cases are inherited. It is caused by mutations in the IKBKG gene (Xq28), which plays an important role in inflammatory, immune, and cellular apoptotic pathways(1). The incidence of the disease is 1/40,000 to 1/50,000 newborns. Clinical findings are highly variable and probably secondary to skewed X-chromosome inactivation in this predominantly female population. The skin, CNS, eyes, teeth, nails, and hair are commonly affected(25).

Clinical manifestations

In incontinentia pigmenti, the hyperpigmented skin marks follow Blaschko’s lines and develop in four stages, beginning at birth or in the first few weeks of life and progressing into adulthood. Retinal vasculopathy and central nervous system involvement are other conditions to watch for.

Skin manifestations

They evolve sequentially in four stages (Fig. 6):

• Stage 1: vesiculobullous: erythematous and vesicular lesions that usually have a linear distribution and present at birth or within the first few weeks of life.

• Stage 2: verrucous; hyperpigmented pustules with crusts develop and last for several months.

• Stage 3: hyperpigmented; swirls of macular hyperpigmentation that may persist into adulthood.

• Stage 4: atrophic/hypopigmented; pale or hairless patches appear on the skin. This stage may be absent in many patients(1,25).

Neurological manifestations

Most neurological problems present in the neonatal or childhood periods and, rarely, at other stages. Ischemic strokes of the middle cerebral artery and anterior cerebral artery, cerebral dysgenesis, cerebellar hypoplasia, cerebral atrophy, hypoplasia of the corpus callosum, and hemorrhagic changes, as well as white matter involvement, have been observed. Between 20% and 40% of patients develop epilepsy, probably secondary to brain malformations and cortical cerebrovascular accidents. Intellectual disability and developmental delay are common.

Ocular manifestations

The most notable are early retinal vasculopathy (the most common abnormality, which can lead to retinal detachment and blindness), optic nerve damage, and asymptomatic corneal abnormalities (cornea verticillata). These manifestations can cause strabismus or nystagmus.

Other demonstrations

Dental abnormalities such as hypodontia, conical teeth, and delayed tooth eruption are described. High arches and cleft palate have a rare but important association with IP and are included as minor diagnostic criteria. Hair abnormalities include sparse hair in childhood, which eventually becomes coarse or fibrous. Alopecia, both of the scalp and the rest of the body, is also present. Nails often appear ridged or severely dystrophic.

Nipple and breast abnormalities are less well characterized. Supernumerary nipples are the most common, but absent nipples, breast aplasia, and asymmetries have also been described(25).

Diagnosis

The diagnosis is based on a series of major and minor clinical criteria, originally by Landy and Donnai, published in 1993 and updated in 2014, after the discovery of the IKBKG gene(25,26) (Table I).

Differential diagnosis

The differential diagnosis to be considered varies depending on the stage of development of the skin lesions, from infections to nevi or warts to pigmentary mosaicism or vitiligo.

It is important to consider the differential diagnosis of cutaneous findings at each stage, such as in childhood, where vesiculobullous lesions similar to those of herpes simplex infection, chickenpox, epidermolysis bullosa, and bullous bacterial infection may appear. The verrucous phase may simulate linear epidermal nevi, verrucous nevi, simple warts, and molluscum contagiosum. The hyperpigmented phase may simulate hypomelanosis of Ito or nonspecific pigmentary mosaicism. The hypopigmented/atrophic phase may resemble various ectodermal dysplasias and vitiligo(25).

Treatment

Treatment for IP will depend on the degree of inflammation present, using corticosteroids, immunosuppressants, and photocoagulation for ocular lesions.

Treatment of skin lesions is symptom-related. Severe inflammatory and verrucous lesions have been treated with topical, oral, and intravenous steroids, as well as topical tacrolimus (except in newborns). Laser treatments have been used for hyperpigmented lesions, but they can cause recurrent inflammation and should generally be avoided.

Neurological manifestations in the neonatal period may require early and aggressive treatment of seizures and microvascular inflammatory changes, for which oral or intravenous methylprednisolone has been used.

In the case of ocular disorders, if retinal vasculopathy is identified, external argon laser photocoagulation can prevent vision loss(25,26).

Prevention

Multidisciplinary care for patients with neurocutaneous syndrome is important. There are various consensus guidelines that determine the most appropriate management for these patients.

The care of a patient with a neurocutaneous syndrome requires a multidisciplinary approach that includes a primary care pediatrician (PCP), geneticist, neuropediatrician, ophthalmologist, dermatologist, neuropsychologist, and occasionally a neurosurgeon and endocrinologist (Table II). Various articles establish specific recommendations for each of the syndromes described, including the necessary radiological controls, the use of electroencephalography as a screening test for the detection of epileptic asymmetries/abnormalities before the onset of epilepsy and its prophylactic treatment, the use of specific drugs such as mTOR or MEK inhibitors, or the need for periodic ophthalmology and dermatology check-ups(6,9,21,22,24,26).

 

Role of the Primary Care Pediatrician

• Early detection of lesions suggestive of NF1, TSC, PWS, and IP, and referral to specialized care.

• To question the presence of cutaneous stigmata in the parents of children with suspicion of these neurocutaneous syndromes.

• It is necessary to know the pathochromy of the different clinical manifestations of the most common neurocutaneous syndromes, so that the pediatrician can contribute to clinical management.

• Many of the children with a neurocutaneous syndrome will present with cutaneous manifestations without other notable symptoms and will be monitored annually by specialist care. The pediatrician should provide appropriate management, with knowledge of the clinical manifestations that may arise and recommend advancing the checkup when deemed appropriate.

• It is necessary to know the precautions or side effects that patients may have due to the use of mTOR pathway inhibitors such as everolimus, or MEK inhibitors such as selumetinib.

 

Conflict of interest

There is no conflict of interest in the preparation of this manuscript or source of funding.

 

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The asterisks show the authors’ opinion of the article’s interest.

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13. Chihi M, Gembruch O, Darkwah Oppong M, Chen B, Dinger TF, Barthel L, et al. Intracranial aneurysms in patients with tuberous sclerosis complex: a systematic review. J Neurosurg Pediatr. 2019; 10: 1-10.

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16. Conte E, Boccanegra B, Dinoi G, Pusch M, De Luca A, Liantonio A, et al. Therapeutic Approaches to Tuberous Sclerosis Complex: From Available Therapies to Promising Drug Targets. Biomolecules. 2024; 14: 1190.

17.** Specchio N, Nabbout R, Aronica E, Auvin S, Benvenuto A, de Palma L, et al. Updated clinical recommendations for the management of tuberous sclerosis complex associated epilepsy. Eur J Paediatr Neurol. 2023; 47: 25-34.

18. Ritter DM, Twardowski S, Franz DN. Treating subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: an update of the literature. Expert Rev Neurother. 2025; 25: 389-96.

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20. Ramirez EL, Jülich K. Sturge-Weber syndrome: an overview of history, genetics, clinical manifestations, and management. Semin Pediatr Neurol. 2024; 51: 101151.

21.*** Shah AD, Alexieff P, Tatachar P. Sturge-Weber Syndrome: A Narrative Review of Clinical Presentation and Updates on Management. J Clin Med. 2025; 14: 2122.

22.** Sabeti S, Ball KL, Bhattacharya SK, Bitrian E, Blieden LS, Brandt JD, et al. Consensus Statement for the Management and Treatment of Sturge-Weber Syndrome: Neurology, Neuroimaging, and Ophthalmology Recommendations. Pediatr Neurol. 2021; 121: 59-66.

23.*** Ruiz-Falcó Rojas ML, González Gutiérrez Solana L, García Peñas JJ, Duat Rodríguez A, Cantarín Extremera V, Soto Insuga V, et al. Síndrome de Sturge-Weber. Sturge-Weber syndrome. Protoc diagn ter pediatr. 2022; 1: 361-7.

24. El Hachem M, Diociaiuti A, Galeotti A, Grussu F, Gusson E, Ferretti A, et al. Multidisciplinary, multicenter consensus for the care of patients affected with Sturge-Weber syndrome. Orphanet J Rare Dis. 2025; 20: 28.

25.*** Rosser T. Incontinentia pigmenti. Semin Pediatr Neurol. 2024; 51: 101156.

26.*** Bodemer C, Diociaiuti A, Hadj-Rabia S, Robert MP, Desguerre I, Manière MC, et al. Multidisciplinary consensus recommendations from a European network for the diagnosis and practical management of patients with incontinentia pigmenti. J Eur Acad Dermatol Venereol. 2020; 34: 1415-24.

Recommended bibliography

– Kioutchoukova I, Foster D, Thakkar R, Ciesla C, Cabassa JS, Strouse J, et al. Neurocutaneous Diseases: Diagnosis, Management, and Treatment. J Clin Med. 2024; 13: 1648.

This article reviews some of the main neurocutaneous syndromes, focusing on the different general manifestations, as well as diagnostic and therapeutic advances.

– Duat-Rodríguez. A. Neurofibromatosis type 1. Pediatr Integral. 2020; 6: 334–41. Available at: https://www.pediatriaintegral.es/publicacion-2020-09/neurofibromatosis-tipo-1/.

Review of the manifestations of neurofibromatosis type 1, highlighting clinical features for early suspicion, even before meeting diagnostic criteria.

– Northrup H, Aronow ME, Bebin EM, Bissler J, Darling TN, de Vries PJ, et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatr Neurol. 2021; 123: 50-66.

Review of the diagnostic criteria for tuberous sclerosis complex, diagnostic tests, and follow-up, highlighting the importance of multidisciplinary work.

– Shah AD, Alexieff P, Tatachar P. Sturge-Weber Syndrome: A Narrative Review of Clinical Presentation and Updates on Management. J Clin Med. 2025; 14: 2122.

Comprehensive approach to the patient with Sturge-Weber syndrome, from cutaneous, neurological, and ocular manifestations to complementary testing, follow-up, and treatment.

– Bodemer C, Diociaiuti A, Hadj-Rabia S, Robert MP, Desguerre I, Manière MC, et al. Multidisciplinary consensus recommendations from a European network for the diagnosis and practical managementof patients with incontinentia pigmenti. J Eur Acad Dermatol Venereol. 2020; 34: 1415-24.

Consensus on the diagnosis, management and follow-up of patients with incontinentia pigmenti.

 

Clinical case

Reason for consultation: an 8-year-old boy came to the clinic with an episode of eye opening, salivation, and right hemifacial clonic spasms lasting approximately 30 seconds while he was sleeping. The child reported hearing them but being unable to speak. He slept well and woke up feeling fine. Over the past month, he has complained of a nonspecific headache without vomiting. He reported no other symptoms. Family history: mother and father were healthy and not consanguineous. After examining the child, a focused questioning was conducted; the father reported similar lesions on his face and several hypopigmented macules, as well as three café-au-lait spots on one leg; he is being treated for high blood pressure. The father’s brother had cognitive impairment and epilepsy in childhood. He had no other relevant medical history. Personal background: normal pregnancy, delivery, and neonatal period. No other relevant data. Physical examination: weight: 24.5 kg (67th percentile); height: 117 cm (42nd percentile); head circumference: 52.5 cm (50th percentile); and blood pressure: 107/52 mm Hg (75th/25th percentile). Good general condition, excellent cooperation, normal expressive and comprehensive language. Cardiopulmonary auscultation was normal. The abdomen was soft with no palpable masses or visceromegaly. The patient had 5 hypopigmented macules, two of a 3 cm lanceolate appearance on the chest and right thigh, and two more rounded, 1 cm diameter lesions on the left arm. Several pink papules were present on the cheeks, and a papular lesion with an orange-peel appearance was present on the lumbosacral region. Cranial nerves were normal, with normal tone and strength. Deep tendon reflexes were present bilaterally with no increase in area. Flexor plantar cutaneous reflex was present. Gait, heels and toes are normal, tandem is normal. No limb differences or tremor.