Phelan-McDermid syndrome: a review of the literature and practice parameters for medical assessment and monitoring.

Alexander Kolevzon,A Ting Wang,Lisa J Edelmann,Lauren Bush,Shubhika Srivastava,Joseph D Buxbaum,Cristina Farrell,Benjamin Angarita,Jeffrey Saland,Amy Yang,Yitzchak Frank,Robert Rapaport

doi:10.1186/1866-1955-6-39

Abstract

Autism spectrum disorder (ASD) and intellectual disability (ID) can be caused by mutations in a large number of genes. One example is SHANK3 on the terminal end of chromosome 22q. Loss of one functional copy of SHANK3 results in 22q13 deletion syndrome or Phelan-McDermid syndrome (PMS) and causes a monogenic form of ASD and/or ID with a frequency of 0.5% to 2% of cases. SHANK3 is the critical gene in this syndrome, and its loss results in disruption of synaptic function. With chromosomal microarray analyses now a standard of care in the assessment of ASD and developmental delay, and with the emergence of whole exome and whole genome sequencing in this context, identification of PMS in routine clinical settings will increase significantly. However, PMS remains a rare disorder, and the majority of physicians have never seen a case. While there is agreement about core deficits of PMS, there have been no established parameters to guide evaluation and medical monitoring of the syndrome. Evaluations must include a thorough history and physical and dysmorphology examination. Neurological deficits, including the presence of seizures and structural brain abnormalities should be assessed as well as motor deficits. Endocrine, renal, cardiac, and gastrointestinal problems all require assessment and monitoring in addition to the risk of recurring infections, dental and vision problems, and lymphedema. Finally, all patients should have cognitive, behavioral, and ASD evaluations. The objective of this paper is to address this gap in the literature and establish recommendations to assess the medical, genetic, and neurological features of PMS.

Highlights

Gene discovery approaches, followed by functional analysis of model systems, have elucidated the neurobiology of several genetic subtypes of autism spectrum disorder (ASD)
With chromosomal microarray recommended as a standard of care for the assessment of ASD [20,21,22,23], it is expected that identification of Phelan-McDermid syndrome (PMS) will increase significantly in routine clinical settings
Chromosomal microarray analysis (CMA) is the first tier in genetic analysis in addition to chromosome analysis to clarify the presence of ring chromosome 22 and translocations

Summary

Introduction

Gene discovery approaches, followed by functional analysis of model systems, have elucidated the neurobiology of several genetic subtypes of autism spectrum disorder (ASD). In at least one child, a unilateral multicystic kidney and Wilms’ tumor in the contralateral, unaffected kidney was detected using prenatal ultrasound [57] As some of these genitourinary abnormalities may result in clinical disease and require treatment, it is recommended that all individuals with PMS have routine blood pressure measurement and renal and bladder sonography performed at the time of diagnosis and, if the sonogram is abnormal, be referred to a pediatric nephrologist or urologist for monitoring or treatment. Because sonography may be normal in cases of vesicoureteral reflux, urinary tract infection at a young age or recurrent urinary tract infections should prompt nephrology or urology referral For those with abnormal renal or bladder sonography or high blood pressure, urinalysis and kidney function blood tests (e.g., urea, creatinine, and electrolytes) should be obtained as the patient is being referred to expert care for additional guidance about specific ongoing monitoring recommendations. Orthodontic or surgical correction of malocclusion may be considered to reduce the risk of tooth decay and periodontal disease or relieve pressure on the temporomandibular joint

Conclusions

Findings

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