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Phakomatoses (also referred to as neurocutaneous syndromes) are a group of genetic and acquired disorders that derive their collective name from the Greek noun phakos ("lentil, spot") and the Greek word terminations -oma (signifying a tumor or neoplasm) and -osis (signifying a process, especially a disease or abnormal process). Phakomatoses are characterized by variable multisystem involvement. Typically, they affect the central nervous system (CNS), the eyes, and the skin, all of which derive from the same ectodermal origin.[1]
Image courtesy of Wikimedia Commons (figure)/Oleksandr Zozulinskyi | Dreamstime (background).
A 10-year-old Pakistani boy presents with a history of progressive ataxia and redness of the eye since the age of 1.5 years. He also has a history of meningitis at the age of 3 years and of recurrent chest infections since the age of 6 years. He has been symptomatically treated for all of these recurrent infections. On examination, he is found to have ocular telangiectasia. There is no lymphadenopathy or hepatosplenomegaly. Cerebellar signs are present. His serum immunoglobulin (Ig) A level is markedly reduced. Magnetic resonance imaging (MRI) of the brain shows cerebellar atrophy.
Which of the following is the most likely diagnosis?
Image courtesy of Wikipedia.
Answer: A. Ataxia-telangiectasia.
A-T is a multisystem autosomal recessive disorder that is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, recurrent sinopulmonary infection, and immunodeficiency.[2] Patients with this disorder have a high risk of malignancy and hypersensitivity to radiation exposure. Serum IgA is deficient in about 70% of cases. IgM levels may be normal to high. Molecular genetic testing shows ATM gene mutation. MRI of the brain often shows nonspecific cerebellar degeneration; cerebellar ataxia (arrow) is apparent in the slide. There is no specific treatment. Infections are treated with appropriate antibiotic therapy.
Image courtesy of Medscape.
A 23-year-old Pakistani man presents to the outpatient department with a 3-year history of bilateral progressive hearing loss, tinnitus, and vertigo. At the time of presentation, he also cites a 4-month history of diffuse headache, blurred vision, and swaying toward either side when walking. He reports that his mother died after being operated on for a brain neoplasm. On general physical examination, the patient has subcutaneous swelling on the right side of his face and also on his back. Neurologic examination reveals a Glasgow Coma Scale (GCS) score of 15/15. His visual acuity is 6/18 on the right side and 6/36 on the left. There is loss of the corneal reflex on the left side, along with bilateral lower motor neuron–type facial palsy and bilateral sensorineural hearing loss. Funduscopic examination reveals bilateral papilledema. The patient exhibits ataxia with bilateral cerebellar signs. MRI of the brain with contrast reveals bilateral rounded well-circumscribed masses at both cerebellopontine angles, which are isointense on T1-weighted imaging (T1WI) and hyperintense on T2-weighted imaging (T2WI) and fluid attenuation inversion recovery (FLAIR) sequences, with patchy postcontrast enhancement.
Which of the following is the most likely diagnosis?
Image courtesy of Shahzad Ahmed, MBBS.
Answer: D. Neurofibromatosis type 2.
NF is a set of three distinct genetic syndromes—namely, NF1 (also known as von Recklinghausen disease), NF2, and schwannomatosis. These are characterized by a variable number of cutaneous lesions, coupled with a range of tumors of the CNS and the peripheral nervous system.[3] Bilateral vestibular schwannomas (arrows), intracranial and spinal meningiomas, and spine tumors are the neoplasms most frequently seen in these patients. Vestibular schwannomas are benign, but whether they are unilateral or (more typically) bilateral, they can lead to progressive sensorineural deafness, vertigo, tinnitus, and balance dysfunction in different combinations.
Image courtesy of Shahzad Ahmed, MBBS.
Other common brain tumors include intracranial meningiomas and ependymomas (arrows). These lead to focal neurologic signs, headache, visual impairment, and seizures. Meningiomas may be single or multiple. These meningiomas (ie, those associated with NF2) arise much earlier than sporadic ones and tend to be more aggressive.
Images courtesy of Medscape.
The diagnosis of NF2 was initially based on the criteria formulated by the National Institutes of Health (NIH). Subsequently, the more sensitive Manchester criteria (shown) were developed as a modification of the NIH criteria[4]; the Manchester criteria are more sensitive and currently are widely used. The clinical diagnosis made on the basis of these criteria can then be confirmed by means of molecular genetic testing for the NF2 gene on chromosome 22.
Table from Evans DG et al.[4]
A 20-year-old Pakistani woman presents to the emergency department (ED) with a history of two episodes of generalized tonic-clonic seizures. She is known to have had epilepsy since early childhood and has been on several different antiepileptic agents, including valproate, levetiracetam, and carbamazepine. She has multiple skin lesions on her face and back. Computed tomography (CT) of the brain shows subependymal calcified nodules noted in the distribution of bilateral lateral ventricles (see slide 10).
Which of the following is the most likely diagnosis?
Image courtesy of Jahangir Shoro, MBBS, FCPS.
Answer: A. Tuberous sclerosis.
TS is an inherited autosomal dominant neurocutaneous disorder. It is a multisystem disease with a diverse range of organ involvement and clinical manifestations.[5] The classic description of TS was based on Vogt's triad, which consisted of intractable seizures, mental retardation, and adenoma sebaceum (ie, facial angiofibromas). However, this concept is now considered outdated. The diagnostic criteria developed by the Tuberous Sclerosis Consensus Conference in 1998, based on specific clinical features, were considered to be more authentic and came to be more widely used; these criteria were subsequently refined at the 2012 International Tuberous Sclerosis Complex Consensus Conference.[6] The brain CT scan in the slide shows the aforementioned subependymal calcified nodules noted in the distribution of bilateral lateral ventricles (arrow).
Image courtesy of Jahangir Shoro, MBBS, FCPS.
At least one characteristic skin lesion of TS is present in more than 95% of cases. The most common of these lesions are angiofibroma, shagreen patch (blue arrow), periungual fibroma (yellow arrow), ash-leaf macule (green arrow), and gingival fibroma (red arrows). Angiofibroma, the most typical of the TS skin lesions, is present on the malar regions of the face and appears between late childhood and early adolescence.
Images courtesy of Jahangir Shoro, MBBS, FCPS (left), and Medscape (right).
A variety of brain lesions may be seen in TS, including cortical tubers, subependymal nodules (SENs), subependymal giant cell astrocytoma (SEGA [arrow]), and white-matter heterotopia. A SEGA typically develops near the foramen of Monro (foramen interventriculare) and may lead to obstructive hydrocephalus. It is treated with administration of sirolimus (rapamycin) and surgical resection.
Image courtesy of Medscape.
A 12-year-old Pakistani boy presents with a history of vision loss in the left eye. On examination, he has café-au-lait pigmentations on his body. Vision in the left eye is reduced to finger counting. There is a relevant afferent pupillary defect on the left side. Funduscopy reveals swelling of the optic nerve head. The family history is positive for epilepsy and skin lesions. MRI of the brain yields findings consistent with left optic nerve glioma (see slide 14).
Which of the following is the most likely diagnosis?
Image courtesy of Medscape.
Answer: B. Neurofibromatosis type 1.
NF1 is a neurocutaneous disorder characterized by pigmented skin lesions, typically café-au-lait spots.[7] Optic pathway tumors are a common manifestation. These may be prechiasmal, chiasmal, or postchiasmal in location and can result in visual loss and blindness. Neurologic involvement can also be seen in the form of CNS tumors (eg, gliomas or glioblastomas), epilepsy, and mental retardation. The brain MRI scan in the slide shows a left optic nerve glioma (arrow). Skeletal involvement is present in 40% of cases of NF1.
Image courtesy of Medscape.
Other commonly seen skin lesions are neurofibromas (blue arrow), axillary freckles (yellow arrow), and inguinal freckles. Lisch nodules may be present in the iris (green arrow). These are hamartomas that often are identified only through slit-lamp examination by an ophthalmologist. Neurofibromas may be discrete or plexiform.
Images courtesy of Medscape.
A 10-year-old boy presents with right-side weakness, seizures, and reddish discoloration on both sides of the face (predominantly the right half). On examination, the port-wine stain has a bilateral distribution that mainly involves the right side of the face. It extends from the forehead and involves both eyelids, the nose, the cheeks, the philtrum, and the upper lip down to the angle of the mouth, from which site it extends to the right ear. The lower lip and the lower jaw are spared. The patient also is found to have pyramidal weakness on the right side with a positive Babinski sign. MRI of the brain shows left cerebral hemiatrophy associated with leptomeningeal angiomatosis (see slide 18).
Which of the following is the most likely diagnosis?
Image courtesy of Medscape.
Answer: C. Sturge-Weber syndrome
SWS is a neurocutaneous disorder consisting of congenital hamartomatous malformations that may involve the eyes, the skin, and the CNS and are characterized by venous angiomas.[8] The hallmark feature is a facial port-wine stain, which is usually unilateral and involves dermatomes supplied by the ophthalmic and maxillary division of the trigeminal nerve. Ocular involvement can manifest as glaucoma, choroidal hemangioma, or buphthalmos. Leptomeningeal angiomas are usually unilateral and parieto-occipital in location; they are mostly calcified and result in seizures, mental retardation, and hemiparesis. The axial T1WI scan in the slide shows left cerebral hemiatrophy (arrow) associated with leptomeningeal angiomatosis.
Image courtesy of Medscape.
A 16-year-old boy presents with a 6-month history of headache. He has previously undergone photocoagulation for angioma of the left retina. On examination, he has a few café-au-lait spots (shown). Neurologic examination is unremarkable, except for bilateral mild papilledema. The basic laboratory panel and abdominal ultrasonography yield normal results. Contrast MRI of the brain shows a well-defined hypervascular enhancing mass (hemangioblastoma; see slide 20).
Which of the following is the most likely diagnosis?
Image courtesy of Wikipedia.
Answer: B. von Hippel-Lindau disease.
VHL disease is a multisystem autosomal dominant disorder that is characterized by a variety of lesions, including the following[9]:
In rare cases, café-au-lait spots may be seen. The hallmark feature is retinal hemangioblastoma, which is visible on direct ophthalmoscopy as a dilated artery leading from the disc to a peripheral tumor with an engorged vein. Most therapies for VHL disease are surgical (ie, tumor excision).
Image courtesy of Medscape.
A 6-month-old girl presents with absent light fixation and weakness of the left side of the body. On examination, hyperpigmented skin lesions are noted, especially on the extremities. Neurologic examination reveals axial hypotonia with left hemiplegia. Slit-lamp examination shows bilateral retinal detachment. CT of the brain shows an acute right middle cerebral artery infarct (see slide 22).
Which of the following is the most likely diagnosis?
Image courtesy of Medscape.
Answer: D. Incontinentia pigmenti.
Incontinentia pigmenti (also referred to as Bloch-Sulzberger syndrome) is a rare neurocutaneous syndrome. It is an X-linked dominant disease that predominantly affects women and can involve the skin, the eyes, hair, the CNS, and the teeth.[10] Cutaneous manifestations are classically divided into the following four stages: (1) erythema and blisters, (2) verrucous lesions and hyperkeratosis, (3) hyperpigmentation, and (4) hypopigmentation. CNS involvement may take the form of hydrocephalus, structural brain abnormalities, or cerebral infarctions presenting as stroke. An axial nonenhanced CT scan of this patient's brain shows an infarct in the territory of the right middle cerebral artery (arrow).
Image courtesy of Shahzad Ahmed, MBBS.
A 22-year-old Pakistani man presents to the neurology clinic with complaints of sharp episodic facial pain on the left side and progressive facial asymmetry after sustaining blunt head trauma at the age of 9 years. On neurologic examination, the left side of the patient's face shows hemiatrophy of facial tissues, especially fat, with a prominent cheekbone and deviation of the angle of the mouth toward the left. Contrast MRI of the brain yields normal findings (see slide 24).
Which of the following is the most likely diagnosis?
Image courtesy of Ali Zohair Nomani, MBBS.
Answer: C. Progressive hemifacial atrophy (Parry-Romberg syndrome).
Parry-Romberg syndrome is an uncommon neurocutaneous disorder that is characterized by a progressive unilateral atrophy of facial tissues.[11] Possible pathogenetic risk factors include trauma and viral infections. Atrophy of skin, subcutaneous tissue, muscles, and bone may be seen. Neurologic manifestations pf progressive hemifacial atrophy include seizures, trigeminal neuralgia, and ipsilateral progressive body atrophy. MRI may yield normal findings (shown).
Image courtesy of Ali Zohair Nomani, MBBS.
A 9-year-old girl presents with the sudden onset of right-side hemiparesis associated with headache and vomiting. Investigations reveal an intraventricular and intracerebral hemorrhage arising from an arteriovenous malformation (AVM) of the left basal ganglia. With conservative management, the patient's symptoms improve, and she is then discharged. After 1 year, she presents again, with a progressive decline in visual acuity detected in the right eye. Retinoscopy shows a retinal AVM (see slide 26). The patient has had several previous episodes of gingival hemorrhage.
Which of the following is the most likely diagnosis?
Image courtesy of Wikipedia.
Answer: B. Bonnet-Dechaume-Blanc (Wyburn-Mason) syndrome.
Bonnet-Dechaume-Blanc syndrome is a congenital, nonhereditary, sporadic disorder characterized by unilateral AVMs of the brain, face, and orbit (arrow).[12] These patients can present with life-threatening intracerebral hemorrhage, epistaxis, gingival bleeding, or visual loss. Angiography is an essential investigation in patients with cerebral and facial AVMs. In most cases, the AVM remains asymptomatic.
Image courtesy of Medscape.
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