Epidermal nevus syndrome with the mutation of PTCH1 gene and cerebral infarction: a case report and review of the literature

Epidermal nevus syndrome (ENS) is a group of congenital neuroectodermal and/or mesodermal disorders characterized by epidermal nevi in association with cerebral, eye, skeletal, cardiovascular, and renal abnormalities [1] that can affect a range of organs. The occurrence of epidermal nevus syndrome is very rare. Solomon et al. reported the first case of epidermal nevus syndrome in 1968 [2]. While diagnostic criteria have not been defined yet, the diagnosis of ENS is mostly clinical. The universal diagnosis is usually based on sebaceous nevus of the scalp, truncus, or extremities present at the time of birth or in early childhood, accompanied by various anomalies of the central nervous system, skeletal system, kidneys, and eyes [3], although central nervous system involvement has been noted to be the most common systemic association with ENS, presenting with a constellation of signs and symptoms ranging from refractory epilepsy to focal motor deficits and developmental delay [4]. Cerebral infarction associated with epidermal nevus syndrome is rare, and the molecular mechanisms of epidermal nevus syndrome spectrum are unclear. We further reviewed the current published case report of ESN and discussed the molecular mechanisms. Recent reports of somatic mosaicism in the pathogenesis of epidermal nevus syndrome have been reported, along with the identification of KRAS and HRAS mutations [5, 6]. So far, only one study has described the deletion of the PTCH gene in association with sebaceous nevus [7]. This case report presents a novel case of epidermal nevus syndrome with a missense mutation in PTCH1 gene and cerebral infarction. To our knowledge, there have been no reports of epidermal nevus syndrome with mutation of PTCH1 gene and cerebral infarction.

We present the case of a 10-month-old Chinese female delivered at a gestational age of 35 weeks following an uneventful pregnancy with parents unrelated to each other. No family history of congenital diseases was found. At birth, she presented with a flat, hairless, yellow-brown linear skin lesion in the right central and temporal scalp, accompanied by brownish-black and verrucose plaques on the right hemifacial and cervical nevi together with the right conjunctival lipomatosus. A skin-colored verrucose tumor was found on the lip, as well as extensive brownish-black plaques and brown nevi on the right side of the trunk and the right arm (Fig. 1). Histopathological examination of the plaque lesions on the hip revealed hyperkeratosis, acanthosis, and sebaceous gland hyperplasia. Renal Doppler ultrasound revealed right kidney enlargement with polycystic kidney. Electrocardiogram suggested premature atrial syndrome. Brain magnetic resonance imaging (MRI) was normal at 3 months of age. Genetic testing was performed in her first month, detecting no pathogenic genes related to the clinical symptoms but one clinically significant variant (PTCH1/NM-000264.3 missense mutation, chr9: 98270535, father source) (Fig. 2).

Ten months later, the patient was referred to our department because of mobility disorder in the right limbs and recurrent seizures. Epilepsy started at 10 months of age and presented with medical refractory seizures, accompanied by quadriplegia, mental retardation, and difficulty swallowing. Blood pressure, electroencephalogram (EEG) recordings, and radiographs of long bones were normal. Cranial computed tomography (CT) scan performed owing to the mobility disorder of the right limbs showed widened sulci in the right parietal lobe. Brain MRI performed owing to the quadriplegia showed cerebral infarction (Fig. 3). Paralysis was aggravated with frequent uncontrollable convulsions during her hospitalization, Her parents gave up therapy on day 11, and the patient was discharged home.

Follow-up was carried out by telephone every 3 months, which involved inquiry about limb motor ability and seizures. Currently, after 9 months of follow-up, the patient is still alive but with severe paralysis, mental retardation, and seizures.

Our patient not only showed the classical pigmented lesions and various developmental abnormalities of multiple organs, but also demonstrated a missense mutation in PTCH1 gene and cerebral infarction. Among the current published case reports of ESN, this case is novel, manifested by epidermal nevus syndrome with a mutation of PTCH1 gene and cerebral infarction.

In accordance with the majority of patients with ENS, the pigmented lesions in our patient are located on the face, neck, truncus, and extremity cutaneous lesions [8], accompanied by various developmental abnormalities of the skin, eyes, and nervous, cardiac, and urogenital systems [9, 10]. Our patient displayed severe neurological clinical manifestations including medical refractory seizures, mental retardation, and severe quadriplegia, indicative of epidermal nevus syndrome [11]. Meanwhile the missense mutation c.109G > T in PTCH1 gene was tested at birth, and cerebral infarction was discovered at 10 months.

The etiology and pathogenesis of epidermal nevus syndrome spectrum is unclear. In terms of the genetic basis of ENS, the published evidence suggests that genomic mosaicism is a basic feature of ENS [12], The genes involved in the pathway include KRAS, HRAS, NRAS, and FGFR1. FGFR2 and FGFR3 mutations have previously been reported to be involved in some cases [6, 13]. In a previous report, the sebaceous nevus was associated with deletions of the PTCH gene [7]. However, PTCH1 gene analyses were not performed in ENS. We provide the first evidence of the involvement of the gene PTCH1 in ENS. However, why did her father have the same missense mutation but no clinical manifestations? Is this an effect of modified genes or environmental factors? Whether the PTCH1 gene is associated with ENS should be addressed in future studies.

Another significant clinical feature of this case was cerebral infarction. Up to now, in literature, several vascular malformations with ENS have been reported: bilateral renal artery stenosis, bilateral vertebral artery occlusion, unilateral renal artery stenosis, coarctation of the aorta, and azygos anterior cerebral artery and internal carotid artery occlusion [1, 14]. Nevertheless, only one case of cerebral infarction has been reported so far [15]. For our patient, brain magnetic resonance angiography (MRA) should have been performed earlier to clarify whether vascular malformation was present. However, her parents refused further inspection and treatment.