Phelan-McDermid syndrome (ORPHA:48652)
A rare genetic neurodevelopmental disorder characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features.
Epidemiology
A rare genetic neurodevelopmental disorder characterized by neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, and minor dysmorphic features.
Clinical description
The severity of the developmental delay tends to vary with deletion size, with most individual functioning in the severe to profound range. Behavior is autistic-like with decreased perception of pain and habitual chewing or mouthing. Major milestones are delayed, receptive language skills typically exceed expressive skills, and many individuals are nonverbal. Other neurological features include seizures, ataxic gait, sleep disturbance, abnormal brain imaging, and regression or loss of skills. Common physical traits include long eye lashes, large or unusual ears, relatively large hands, dysplastic toenails, full brow, dolicocephaly, full cheeks, bulbous nose, and pointed chin. Between 10 to 25% of individuals have gastrointestinal reflux, cardiac abnormalities renal anomalies, lymphedema, or visual defects.
Etiology
The majority of cases result from the loss of 22q13.3 due to a simple deletion, translocation, ring chromosome or other structural chromosome changes involving the SHANK3 gene (PMS-SHANK3 related). About 15% of people have a heterozygous pathogenic variant in the SHANK3 gene. Less frequently, an individual may have an interstitial deletion of 22q13 that does not involve the SHANK3 gene (PMS-SHANK3 unrelated).
Diagnostic methods
The diagnosis of monosomy 22q13.3 syndrome should be considered in all cases of hypotonia of unknown etiology and in individuals with absent speech. Chromosomal microarray is recommended as the first tier of testing. Detection of pathogenic variants of SHANK3 requires gene testing (genome sequencing, exome sequencing).
Differential diagnosis
Differential diagnosis includes syndromes associated with hypotonia, developmental delay, speech delay and/or autistic-like behavior (Prader-Willi, Angelman, Williams, Smith-Magenis, fragile X, Sotos, FG, and velocardiofacial syndromes, autism spectrum disorders and cerebral palsy).
Antenatal diagnosis
Antenatal diagnosis is possible where a parental chromosome rearrangement or pathogenic variant has previously been identified. Because of the difficulty detected parental mosaicism, antenatal diagnosis may also be offered to parents of children with apparently de novo deletions or pathogenic variants.
Genetic counseling
Transmission is autosomal dominant; while most cases occur sporadically, genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy. The risk of affected offspring is also increased for parents who carry balanced structural abnormalities of chromosome 22. The risk to a translocation carrier depends on the type of chromosome abnormality, the size of the chromosome segments involved, the mode of ascertainment, the sex of the transmitting parent, and other factors. Most risk estimates will fall below 30%.
Management and treatment
Individuals with monosomy 22q13.3 should have routine examinations by the primary care physician, as well as genetic evaluations with referral to specialists if neurological, gastrointestinal, renal, or other systemic problems are suspected. Affected individuals benefit from early intervention programs, intense occupational and communication therapies, adaptive exercise and sport programs, and other therapies to strengthen their muscles and increase their communication skills. Because ring chromosome 22 is associated with a specific risk of neurofibromatosis type 2 (NF2), individuals ring 22 must undergo increased surveillance for symptoms of NF2.
Prognosis
No apparent life-threatening organic abnormalities accompany the diagnosis of monosomy 22q13.3.

                            Last update: 
                            July 2024


                            - Expert reviewer(s): 
                            Dr Katy PHELAN