Dear Editor,
Nevoid basal cell carcinoma syndrome (NBCCS; also called Gorlin-Goltz syndrome, MIM:
109400) is a rare autosomal dominantly inherited disorder caused by defects in the
hedgehog signaling resulting in constitutive pathway activity and tumor cell proliferation.1
In addition to basal cell carcinoma from a young age, distinguishing features are
keratocystic odontogenic tumors, dyskeratotic palmar and plantar pitting, skeletal
and other developmental abnormalities, and neurological involvement (e.g., meningeal
calcifications, intracranial tumors, seizures, congenital hydrocephalus, intellectual
disability, and movement disorders).1
2 Here we report two patients with unusual neurological presentations of NBCCS. Written
informed consent was obtained from both patients, and their family histories were
negative.
A 24-year-old female was referred because of bilateral frontal-temporal headache of
mild-to-moderate intensity without signs of increased intracranial pressure and which
responded to non-steroidal anti-inflammatory drugs with short-lasting relief. She
had a prenatal diagnosis of macrocephaly with mild ventriculomegaly and a mild delay
in motor development, but no intellectual disability. She had undergone surgery for
keratocystic odontogenic tumors in her infancy. A physical examination revealed a
prominent forehead, mild hypertelorism, macrocephaly (head circumference 60 cm, ≥97th
percentile), mandibular prognathism, and pits on the palms (Fig. 1A). The findings
of a neurological examination were normal. Extensive laboratory testing, including
of pituitary and parathyroid hormones, produced negative results. Electroencephalography
(EEG) results were also normal, and skeleton X-rays and cardiac and pelvic ultrasonography
produced unremarkable findings. A maxillofacial computed tomography (CT) scan revealed
a cystic lesion in the body of the left mandible (Fig. 1B). Head CT showed diffuse
calcifications of the falx cerebri and tentorium cerebelli (Fig. 1C), and a microadenoma
of the pituitary gland and a choroid plexus papilloma of the left lateral ventricle
were evident in magnetic resonance imaging (MRI). Dermoscopy showed multiple melanocytic
nevi (Fig. 1D) and a basal cell carcinoma of the trunk (Fig. 1E). PTCH1 mutations
were ruled out.
The second patient, a 16-year-old female, was admitted because of developmental delay
and behavioral disturbances. She had previously received surgery for two nodular basal
cells carcinomas below the eyelids (Fig. 1F). Her full IQ was 55 on the Wechsler Intelligence
Scale for Children (revised edition). A physical examination revealed short stature
(height 158 cm, ≤3rd percentile), prominent eyebrows, scapular winging, and marked
scoliosis of the dorsal-lumbar spine with hyperkyphosis of the dorsal tract. A neurological
examination disclosed moderate-to-severe intellectual disability, stereotypical motor
behavior (e.g., swinging and clapping the hands), and sphincter incontinence. Several
hyperpigmented basal cell carcinomas were observed over her face, especially around
the eyes (Fig. 1G). Dermoscopy also revealed multiple pits on the palms and a melanocytic
nevus of the right shoulder. The findings of laboratory, cardiac, and pelvic examinations
were normal. EEG excluded epileptic abnormalities. X-rays showed three bifid ribs
on the right side and bilateral mandible cystic lesions. Brain CT showed calcification
of the falx cerebri (Fig. 1H). The patient did not cooperate with MRI, and refused
genetic testing.
Both the phenotype and imaging results for these patients supported the clinical diagnosis
of NBCCS. It was particularly interestingly that they had first sought neurologist
attention, which highlights the importance of the awareness of this multifaceted neurocutaneous
disorder and a multidisciplinary approach.1 Although diagnostic criteria for NBCCS
have been established,3 the racial and genetic background may contribute to different
levels of expressivity, even within the family.4 It is worth remembering that headache
in NBCCS–in the absence of disease-related causes (e.g., medulloblastoma, meningioma,
and hydrocephalus)–might be coincidental. Similarly, intracranial calcifications,
which are rare in young patients, can be due to trauma, infection, meningioma, or
hypoparathyroidism (which were all excluded in the present cases).
In conclusion, neurological and neuroimaging findings associated with NBCCS might
be crucially important for obtaining a better pathophysiological understanding, an
early diagnosis, and appropriate management of the related malignancy. The take-home
message is that neurologists should examine the skin and bones of patients with meningeal
calcifications.