Phelan-McDermid syndrome and neurofibromatosis type 2

Lyons-Warren AM, Cheung SW, Holder JL Jr. Clinical Reasoning: A common cause for Phelan-McDermid syndrome and neurofibromatosis type 2: One ring to bind them. Neurology. 2017 Oct 24;89(17):e205-e209.

An 8-year-old girl with mild dysmorphic features presented for evaluation of developmental delay and staring spells. She had been born late preterm and spent 1 month in the neonatal intensive care unit. She was generally healthy other than her developmental delay, which improved somewhat with physical, occupational, and speech therapy. At the first clinic visit, her mother reported loss of previously mastered vocabulary and struggles with fine motor skills such as buttoning. She also noted repetitive movements, obsessive behaviors, and hand flapping…

Our patient's initial evaluation included an MRI brain that was unremarkable and a karyotype that revealed a ring chromosome 22 including a terminal deletion of the long arm. A ring chromosome is when the p and q arms of the chromosome fuse together and often occurs due to deletion of one arm. Subsequent high-resolution karyotype with subtelomeric fluorescent in situ hybridization analysis confirmed the diagnosis and demonstrated a double-sized ring chromosome 22 in 15% of cells. In order to better define the size of the deletion, a high-resolution aCGH was performed, which identified a 1.036-Mb deletion in the subtelomeric region of the long arm of chromosome 22 involving 20 genes including SHANK3, consistent with the diagnosis of Phelan-McDermid syndrome (PMS).

After receiving the diagnosis, the patient was lost to follow-up for several years. At age 16, the family noted a change in the patient's personality. She previously related well with other children and was described as sweet and kind. Her parents expressed concern for new episodes of unprovoked anger. Her family also noted the development of painless growths on both arms, most predominant on the left arm and wrist…

Brain MRI revealed a large, enhancing right cerebellopontine angle to internal auditory canal vestibular schwannoma and a punctate contralateral vestibular schwannoma that were not present on the prior brain MRI brain at 8 years of age. Based on these findings, MRI spine was also ordered and identified enhancing foci in multiple paraspinal areas, which were concerning for schwannomas. EEG revealed a focus of sharp transients over the left temporal region suggestive of an epileptogenic focus. The patient subsequently had an event concerning for seizure in which she was staring and nonresponsive and then fell to the ground. Audiology testing was not able to establish hearing sensitivity due to the patient's inability to complete the task. However, crossed acoustic reflexes were absent, suggesting impairment of the auditory nerve.

Given the presence of bilateral vestibular as well as spinal schwannomas, the growths on her arms were likely peripheral schwannomas. The patient was referred to oncology for further evaluation. She was determined to meet criteria for neurofibromatosis type 2 (NF2). Comprehensive auditory evaluation was difficult to obtain secondary to the patient's intellectual disability. She was evaluated by neurosurgery, who did not recommend surgical intervention as hearing was intact to voice. She was treated with bevacizumab with significant improvement in her mood and monitored with serial brain imaging every 3 months and serial spine imaging every 6 months. An ophthalmologic consultation was obtained to evaluate for ocular findings of NF2, such as cataracts, orbital meningiomas, and retinal hamartomas, which were absent.

PMS, or 22q13.3 deletion syndrome, is a rare neurologic syndrome characterized by global developmental delay leading to moderate to severe intellectual disability with severe language impairment. Additional features include poor eye contact, anxiety, and reduced social interactions consistent with autism spectrum disorder. Dysmorphic features on physical examination can include large fleshy hand, bulbous nose, long eyelashes, hypoplastic nails, dysplastic ears, and dolichocephaly as well as neonatal hypotonia. Baseline renal ultrasound is recommended as more than one-quarter of children will have renal abnormalities ranging from reflux to absent kidneys. Individuals with PMS may also have developmental structural brain abnormalities, including delayed myelination, thin corpus callosum, and arachnoid cysts. Finally, children with PMS can have sleep abnormalities, including bedtime resistance, delayed onset, sleep anxiety, parasomnias, sleep-disordered breathing, and daytime sleepiness.

Patients with PMS can have variable phenotype possibly related to size of their deletion on the long arm of chromosome 22.5 The majority of neurologic features, however, are believed to be due to haploinsufficiency of the SHANK3 gene.6 The SHANK3 protein is enriched in the postsynaptic density of excitatory synapses. Along with other members of the SHANK protein family, SHANK3 is believed to play an important role in synaptogenesis, synapse maintenance, and synapse plasticity.

NF2 is diagnosed using the Manchester criteria:

Bilateral vestibular schwannomas or

Unilateral vestibular schwannoma and at least 2 other features including meningioma, glioma, schwannoma, or juvenile posterior lenticular opacities

The hallmark feature is bilateral vestibular schwannomas. However, additional criteria allow for the diagnosis in a patient with at least 2 meningiomas and unilateral vestibular schwannoma or at least 2 meningiomas and 2 of the other features including glioma, neurofibroma, schwannoma, and cataract.7 Although schwannomas are benign, they can cause symptoms ranging from hearing loss to brainstem compression and are therefore usually monitored with serial imaging. These symptoms are caused by disruption of the NF2 gene on chromosome 22 (figure, C), which codes for merlin protein.

Ring chromosomes were first described by Lilian Morgan in 1926 and have been reported for all chromosomes. Terminal deletions can result in a ring chromosome when the truncated arm fuses with another end and forms a ring. Ring chromosomes are mitotically unstable, leading to somatic loss and resultant mosaicism. When the ring is lost during mitotic cell division, cells become monosomic for the affected chromosome. There are multiple reports of patients with ring chromosome 22, all of whom shared features of PMS, including speech delay, seizures, and autism. Rearrangements of chromosome 22, including ring 22, have also been reported to cause NF2. In the case of ring chromosome 22 due to a large, terminal deletion like in our patient, cells become monosomic for chromosome 22, and then have only 1 copy of NF2. In patients with NF2 secondary to ring chromosome 22, it is possible that aspects of their phenotype are related to mosaicism of SHANK3 haploinsufficiency. We therefore recommend that children diagnosed with PMS through aCGH should be evaluated for ring chromosome by karyotype. If ring 22 is present, they should be evaluated as recommended for children of affected parents, who have a 50% risk of developing NF2.