Clinical characteristics.

Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate-to-profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguish Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.

Diagnosis/testing.

The diagnosis of Phelan-McDermid syndrome is established in a proband with typical clinical findings by detection of a heterozygous deletion of chromosome 22q13.3 with involvement of at least part of SHANK3 or of a heterozygous pathogenic variant in SHANK3 on molecular genetic testing. Individuals diagnosed by chromosomal microarray should have a karyotype to evaluate for the presence of a ring chromosome 22.

Management.

Treatment of manifestations: Early referral for developmental support / special education; assistive technology for communication, oral-motor therapy to alleviate chewing and swallowing problems; standard treatment of seizures, hearing loss, recurrent ear infection, visual problems, and other identified medical needs. Regular professional dental hygiene, routine brushing, and fluoride treatment are important as enamel may be damaged from persistent chewing.

Surveillance: Evaluation by a neurologist for epilepsy or if changes in behavior or regression of skills become evident; monitoring for lymphedema, which may appear in adolescence or adulthood; monitoring for symptoms of neurofibromatosis type 2 (NF2) in individuals with ring chromosome 22.

Agents/circumstances to avoid: Exposure to high temperatures and extended periods in the sun because of decreased perspiration; exposure to dangers such as sources of excessive heat or cold, sharp objects, or clothes/shoes that are too tight, due to decreased perception of pain.

Genetic counseling.

Phelan-McDermid syndrome, caused by a deletion of 22q13.3 that includes at least a part of SHANK3 or a pathogenic variant in SHANK3, is inherited in an autosomal dominant manner. The deletion may be de novo or the result of a balanced translocation in one of the parents; pathogenic variants in SHANK3 are almost always de novo. Prenatal testing and preimplantation genetic testing for Phelan-McDermid syndrome are possible for a pregnancy at increased risk.

Suggestive Findings

Phelan-McDermid syndrome should be suspected in children with the following:

• Neonatal hypotonia
• Absent to severely delayed speech
• Developmental delay
• Minor dysmorphic facial features including:
  • Dolichocephaly
  • Full brow
  • Flat midface
  • Deep-set eyes
  • Full or puffy eyelids
  • Long eyelashes
  • Wide nasal bridge
  • Bulbous nose
  • Full or puffy cheeks
  • Large or prominent ears

Other features that raise suspicion of Phelan-McDermid syndrome include relatively large and fleshy hands, dysplastic toenails, sacral dimple, and decreased perspiration. As most autosomal chromosome disorders are associated with short stature with or without small head size, normal stature and normal head size distinguish Phelan-McDermid syndrome from other autosomal disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.

Of note, most individuals with Phelan-McDermid syndrome are identified by chromosomal microarray analysis (CMA) performed in the context of evaluation for developmental delay, intellectual disability, and/or autism spectrum disorder.

Establishing the Diagnosis

The diagnosis of Phelan-McDermid syndrome is established in a proband with typical clinical findings and detection of:

• A <50-kb to >9-Mb heterozygous deletion at chromosome 22q13.3 with involvement of at least part of SHANK3; OR
• A heterozygous pathogenic (or likely pathogenic) variant in SHANK3 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous SHANK3 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular testing approaches can include chromosomal microarray analysis (CMA), single-gene testing, and use of a multigene panel:

• Chromosomal microarray analysis (CMA). CMA should be the first genetic test as most cases of Phelan-McDermid syndrome are caused by large copy number variants (CNVs), which cannot be detected by sequence analysis of SHANK3. It is imperative that detection of deletions by CMA be followed by karyotype screening for ring chromosome detection.
• Single-gene testing. Gene-targeted deletion/duplication analysis of SHANK3 is performed first and followed by sequence analysis of SHANK3 if no deletion is found.
• A multigene panel that includes SHANK3 and other genes of interest (see Differential Diagnosis) may be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Clinical Description

Males and females are equally affected with no apparent parent-of-origin effect (Table 2).

Hypotonia. Newborns with Phelan-McDermid syndrome have generalized hypotonia that may be associated with weak cry, poor head control, and feeding difficulties leading to slow growth.

Developmental delay. Most individuals with Phelan-McDermid syndrome are described as having "global developmental delay" or "moderate-to-profound intellectual disability." Although the severity of the delay tends to vary with deletion size [Sarasua et al 2011, Zwanenburg et al 2016], individuals with the same size deletion may be vastly different in their degree of disability [Dhar et al 2010]. Development assessment using the Developmental Profile II (DPII) and the Scales of Independent Behavior-Revised – Full Scale (SIB-R) demonstrated that while all participants in the study of Wilson et al [2003] had moderate to profound intellectual disability, compared to most children with this level of impairment, those with Phelan-McDermid syndrome had less frequent and less severe problematic behaviors. In an independent study based on the Bayley-II-NL scale of infant development, Zwanenburg and colleagues [2016] reported developmental delay with a maximum developmental age equivalent of 3 to 4.5 years and more pronounced delays in older individuals than in younger children, a trend referred as "growing into deficit."

Major milestones are delayed: the average age for rolling over is approximately eight months, for crawling approximately 16 months, and for walking approximately three years. Poor muscle tone, lack of balance, and decreased upper body strength contribute to the delay in walking. Gait is typically broad-based and unsteady. Individuals may walk on their toes to achieve balance.

Toilet training is difficult to achieve and requires extreme vigilance by parents and caregivers. Children may stay dry at night but become wet or soiled during the day because they are unable to communicate their needs.

Neurologic. Arachnoid cysts occur in approximately 15% of individuals with Phelan-McDermid syndrome compared to an estimated 1% in the general population. Other neurologic problems include reduced myelination, frontal lobe hypoplasia, agenesis of the corpus callosum, ventriculomegaly, focal cortical atrophy, and seizures [Tabolacci et al 2005].

Brain imaging studies on eight children with Phelan-McDermid syndrome revealed normal MRI in three children with the smallest deletion size; four of the remaining five had thinning of the corpus callosum; and one of the five had atypical morphology of the corpus callosum [Philippe et al 2008]. PET studies of the eight children demonstrated localized dysfunction of the left temporal polar lobe and significant hypoperfusion of the amygdala compared to 13 children with idiopathic intellectual disability.

Between 25% and 50% have seizures, many of which are febrile and do not require medication; however, grand mal seizures, focal seizures, and absence seizures have been described. No characteristic EEG findings are associated with Phelan-McDermid syndrome.

Neurologic and motor regression has been reported by a number of parents of individuals with Phelan-McDermid syndrome. Loss of speech is most frequently reported but loss of self-help skills, social interactions, purposeful hand movements, and walking have also been described. In a study of 42 individuals age four to 48 years, Reierson et al [2017] found that parents reported regression in 43% of individuals with onset around age six years. About 40% of individuals recovered skills; time to recovery ranged from one month to ten years. The ADI-R was used to characterize the regression and reported loss of:

• Motor skills in 50% at mean age 4 years
• Self-help skill in 50% at mean age 4 years
• Language in 33% at mean age 3 years
• Social engagement/responsiveness in 33% at mean age 5 years
• Purposeful hand movement in 28% at mean age 7 years
• Constructive/imaginative play in 22% at mean age 7 years

The regression in Phelan-McDermid syndrome is distinct from the regression seen in autism and Rett syndrome in that it occurs later in life and has a stronger impact on motor skills and self-help skills [Reierson et al 2017].

Behavior. Philippe et al [2008] examined the neurobehavioral profiles of eight children with Phelan-McDermid syndrome who ranged in age from four years, three months to 11 years, four months. Behavior problems included hyperactivity, short attention span, restlessness, clumsiness, ignorance of the consequences, resistance to change, and repetitive activities.

Other abnormal behaviors described in Phelan-McDermid syndrome include habitual chewing or mouthing, tooth grinding, decreased perception of pain, and sleep disturbance. Although sleep apnea is not a problem, affected individuals may have difficulty falling asleep and staying asleep. Affected individuals may become agitated in unfamiliar, noisy, or crowded surroundings.

While Philippe et al [2008] concluded that behavior exhibited by children with Phelan-McDermid syndrome did not meet the DSM IV criteria for autism spectrum disorder (ASD), other investigators have described the behavior as autistic or autistic-like with poor eye contact, stereotypic movements, and self-stimulation. More recently, Soorya et al [2013] reported in a cohort of 32 individuals with Phelan-McDermid syndrome a high rate of individuals meeting criteria for autism spectrum disorder (84%) and for autistic disorder (75%). Oberman et al [2015] evaluated the behavioral profile of 40 children with Phelan-McDermid syndrome and noted that the majority of individuals displayed persistent deficits in social communication, but only half met diagnostic criteria under the restricted, repetitive patterns of behavior, interests, or activities domain. Furthermore, logistic regressions indicated that general developmental delay significantly contributed to the ASD diagnosis.

As a result of decreased perception of pain and lack of expressive communication skills, affected individuals may suffer cuts, scrapes, or even broken bones without indicating that they are in pain. They may suffer ear infections, gastroesophageal reflux, increased intracranial pressure, or other painful medical conditions without indicating discomfort.

Aggressive behavior including biting, hair pulling, or pinching is seen in approximately 25% of affected individuals. The behavior is typically displayed when individuals are frustrated and may indicate that they are in pain but cannot express themselves appropriately. The behavior is not self-injurious but is often directed at the parent or caregiver.

Speech delay. Infants typically babble at the appropriate age and children may acquire a limited vocabulary. However, by approximately age four years many children have lost the ability to speak. With intensive occupational, speech, and physical therapy they may regain speech and increase their vocabularies. Physical therapy strengthens muscle tone, improves coordination, and generally increases the individual's awareness of his/her surroundings. Although speech remains impaired throughout life, individuals can learn to communicate with the aid of aggressive therapy and communication training.

Receptive communication skills are more advanced than expressive language skills as evidenced by the ability of affected children to follow simple commands, demonstrate humor, and express emotions.

Hearing. Individuals with Phelan-McDermid syndrome have a delayed response to verbal cues. They also have difficulty discerning spoken words from background noise. These two factors, along with the frequent occurrence of ear infections, contribute to the perception that hearing may be impaired. In fact, more than 80% of affected individuals have normal hearing.

Vision. Most affected individuals have normal vision, although hyperopia and myopia are observed. Cortical visual impairment, characterized by extensive use of peripheral vision, difficulty in processing cluttered images, problems with depth perception, and the tendency to look away from objects before reaching for them, has been reported in approximately 6% of affected individuals. The quality of vision fluctuates. Blindness and optic nerve hypoplasia have been associated with cortical visual impairment [Phelan et al 2010].

Gastrointestinal. Gastroesophageal reflux is seen in approximately 30% and cyclic vomiting in approximately 25% of individuals. Constipation and diarrhea are also reported. Precautions must be taken to avoid dehydration.

Renal. The frequency of renal abnormalities has been reported as high as 38% [Soorya et al 2013]. These include cystic kidneys, renal agenesis or dysplastic kidneys, hydronephrosis, vesicoureteral reflux, horseshoe kidney, and pyelectasis. Frequent urinary tract infections are also reported.

Growth. Intrauterine growth in Phelan-McDermid syndrome is appropriate for gestational age; the mean gestational age is 38.2 weeks. Postnatal growth is normal. Height is often advanced for age but remains within two to three standard deviations from the mean. Weight is not increased so children appear tall and thin.

Whereas children may have increased height for age, adults tend to fall within the normal range for height. Most adults are also within the normal range for weight, although inactivity and overeating (possibly a manifestation of compulsive mouthing) result in increased weight gain in approximately 10% of individuals.

Head size is typically within normal range with microcephaly reported in about 11% of individuals [Rollins et al 2011].

Hypothyroidism occurs in 3%-6% of individuals with this disorder [Soorya et al 2013, Sarasua et al 2014b]. Symptoms include lethargy, loss of interest, weight gain, and decline in skills and are typically manifested in the teenager or young adult. A thyroid panel should be obtained to rule out hypothyroidism.

Dental. The most frequently encountered dental problems are malocclusion and crowding. Poor muscle tone, incessant chewing, tooth grinding, and tongue thrusting may contribute to malocclusion. Malocclusion may be accompanied by drooling and difficulty swallowing, and may contribute to difficulties in verbalization.

Lymphedema. Both lymphedema and recurrent cellulitis have been observed in approximately 10% of individuals, typically becoming problematic during the teen and adult years. Progressive lymphedema leading to pleural effusions has been reported in a female with Phelan-McDermid syndrome resulting from a ring chromosome r(22)(p11.2q12.3) [McGaughran et al 2010].

Craniofacial. Among the most common and striking craniofacial features are dolichocephaly, large or prominent ears, epicanthal folds, long eyelashes, supraorbital fullness, full cheeks, and short or bulbous nose. More subtle features are deep-set eyes, flat midface, full brow, and wide nasal bridge. The features may change over time, particularly if the individual is on anticonvulsants that tend to coarsen the features. Adults have a more prominent, square jaw and less bulbous-appearing nose.

Cardiac. Various congenital heart defects have been reported, including aortic regurgitation, patent ductus arteriosus, total anomalous venous return, atrial septal defect, and tricuspid valve regurgitation; estimates of the incidence of congenital heart defects range from 3% to 25% [Phelan & McDermid 2012, Soorya et al 2013, Kolevzon et al 2014a]. Kolevzon et al [2014a] recommend that the initial workup of an individual with Phelan-McDermid syndrome include a standard cardiac evaluation with echocardiograph and electrocardiography to detect defects requiring medical and/or surgical intervention.

Other

• The hands appear large and fleshy.
• Toenails are often dysplastic, thin, and flaky and tend to become ingrown. Fingernails are usually normal.
• An atypical teratoid/rhabdoid tumor has been reported in at least three cases: an infant with a 7.2-Mb deletion of 22q13 [Sathyamoorthi et al 2009], a girl age four years with a ring 22 [Rubio 1997], and a boy age four months with a ring 22 [Cho et al 2014].
• Arylsulfatase A deficiency (metachromatic leukodystrophy) was observed in a child with deletion 22q13 and mutation of ARSA on the homologous chromosome 22 [Bisgaard et al 2009].

Adulthood. Longitudinal data are insufficient to determine life expectancy. However, life-threatening or life-shortening cardiac, pulmonary, or other organ system defects are not common. The paucity of older adults with Phelan-McDermid syndrome reflects the difficulty in establishing the diagnosis prior to the advent of high-resolution chromosome analysis, FISH, and CMA.

In older individuals, behavioral problems tend to subside, developmental abilities improve, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints are reported as less frequent [Sarasua et al 2014b]. Late-onset seizures, unexplained weight loss, and loss of motor skills may occur in older individuals, adversely affecting quality of life.

Ring chromosome 22. Individuals with Phelan-McDermid syndrome as a result of ring chromosome 22 have a specific risk of developing neurofibromatosis type 2 (NF2).

NF2 (pathogenic variants in which cause NF2) is at 22q12.2 adjacent to the Phelan-McDermid syndrome deletion region. The risk for NF2 is due to the instability of ring chromosomes during mitosis and follows a two-hit model. The first hit is the loss of the ring chromosome 22 during mitosis, making a cell hemizygous for chromosome 22. The second hit is a somatic mutation of the remaining NF2 allele [Zirn et al 2012].

Children with ring chromosome 22 should be monitored for NF2 in the same manner as if they had an affected parent. This includes baseline and annual ocular, dermal, and neurologic examinations between ages two and ten years with annual audiology screening and brain MRI every two years after age ten years [Lyons-Warren et al 2017].

Mosaic 22q13.3 deletion. Mosaic 22q13.3 deletion has been reported on occasion. The level of mosaicism for 22q13.3 deletion varies among affected individuals. Note: Because most testing is performed on blood samples, because the level of mosaicism in blood can change over time, and because the level of mosaicism in the blood is not representative of the level of mosaicism in the brain and other tissues, the level of mosaicism that is sufficient for expression of the major features of Phelan-McDermid syndrome is unknown.

Mosaicism is particularly common in 22q13 deletion associated with ring chromosomes because of the instability of the ring structure during cell division.

• One adult with characteristic features of Phelan-McDermid syndrome showed ring 22 in only 8% of blood cells [Phelan, unpublished data].
• Bonaglia et al [2009] reported mosaicism for ring chromosome 22 in two individuals with deletions of 8.8-8.9 Mb. The first individual had a ring derived from the maternal chromosome 22 in 45% of cells as well as paternal isodisomy for the segment 22q13.2-qter, which resulted from gene conversion in the cells that did not have the ring chromosome 22. The second individual had a ring derived from the paternal chromosome 22 in 73% of peripheral blood cells. Psychomotor delay was more severe in the second individual than in the first.

In at least three instances mosaicism in asymptomatic mothers resulted in Phelan-McDermid syndrome in their offspring:

• Two brothers with features suggestive of Clark-Baraitser syndrome (see Differential Diagnosis) were found to have deletion of approximately 3.5 Mb at 22q13. It was inferred that the deletion had been inherited from the mother because the brothers had not inherited the same paternal chromosome 22 [Tabolacci et al 2005].
• A phenotypically normal mother of two affected children was mosaic for deletion 22q13.3, resulting from an unbalanced translocation with the satellite region of an unidentified acrocentric chromosome. The derivative chromosome 22 was observed in 6% of cells from maternal peripheral blood [Phelan, unpublished data].
• The mother of a child with non-mosaic ring chromosome 22 had ring chromosome 22 in fewer than 2% of peripheral blood cells [Phelan, unpublished data].

Genotype-Phenotype Correlations

Although several studies to determine genotype-phenotype correlations in those with Phelan-McDermid syndrome failed to show a relationship between deletion size and severity of features, the study by Wilson et al [2003] reported a statistically significant correlation between deletion size and the degree of developmental delay and severity of hypotonia.

More recent analyses indicated that larger deletions were associated with increased likelihood of dysmorphic features and medical comorbidities, while small deletions or SHANK3 pathogenic variants correlated with autism spectrum disorder, seizures, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features [Soorya et al 2013]. Sarasua et al [2014a] and Sarasua et al [2014b] confirmed the trend correlating larger deletions with more severe clinical presentations and smaller deletions with autism spectrum disorder, and also identified specific loci and candidate genes within the 22q13.2q13.32 region associated with certain features of the Phelan-McDermid syndrome: severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. Although there is a tendency for larger deletions to be correlated with more severe intellectual and physical phenotypes than smaller deletions, the correlation is not 100%; individuals with the same size deletion may vary significantly in their presentation [Dhar et al 2010].

Penetrance

Although it was previously thought that features of Phelan-McDermid syndrome were apparent in all individuals with non-mosaic 22q13.3 deletion that include SHANK3, recent evidence suggests that small deletions involving SHANK3 may be associated with non-penetrance and variable expressivity (see Tabet et al [2017]). Pathogenic variants in SHANK3 have been associated with Phelan-McDermid syndrome, nonsyndromic autism, and schizophrenia.

• Tabet et al [2017] described a multiplex family in which the mother and five of six daughters had a 67-kb deletion of SHANK3. The proband was diagnosed with Phelan-McDermid syndrome and her sisters had delayed speech with or without mild to moderate intellectual disability. CNVs of two other genes, NRXN1 and KAL1, were also segregating in the family and were thought to contribute to the phenotypic variability, perhaps by modulating the effect of the SHANK3 deletion.
• Full manifestation of features has been seen in individuals with as low as 8% mosaicism for the 22q13.3 deletion in peripheral blood [Phelan, personal observation].

Nomenclature

Previously referred to as 22q13.3 deletion syndrome to reflect the chromosomal basis of this deletion, the condition is now commonly called Phelan-McDermid syndrome, a more comprehensive term that includes individuals with 22q13.3 deletion and those without a detectable deletion who have a pathogenic variant in SHANK3.

Prevalence

The prevalence of Phelan-McDermid syndrome is unknown. More than 1,500 individuals are registered with the Phelan-McDermid Syndrome Foundation (Venice, Florida, 2017). This does not represent the total number of affected individuals, as not all families worldwide register with the foundation.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Phelan-McDermid syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

Treatment is symptomatic; no specific therapy is available. The following are appropriate interventions.

Surveillance

Note: It is not intuitive that individuals with a deletion of chromosome 22q13 would be at risk for NF2, but those with a ring chromosome are at significant risk.

• If the diagnosis of Phelan-McDermid syndrome associated with a deletion of chromosome 22q13 was made by chromosomal microarray analysis (CMA), a follow-up karyotype is necessary to see if a ring chromosome is present.
• If a ring chromosome is present, the individual should have a baseline ocular, dermal, and neurologic examination.
• Between ages two and ten years, annual ocular, dermal, and neurologic exams should be performed.
• After age ten years, additional audiologic screening should be performed annually and a brain MRI performed every two years.

Agents/Circumstances to Avoid

Exposure to high temperatures and extended periods in the sun should be avoided because individuals with Phelan-McDermid syndrome have reduced perspiration and tend to overheat easily.

Considering that individuals with Phelan-McDermid syndrome may present with decreased perception of pain, close surveillance is recommended to prevent exposure to dangers including sources of excessive heat or cold, sharp objects, or clothes/shoes that may be too tight and cause skin lesions.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Lithium. Lithium has been used to treat behavioral issues in three affected individuals. First, Serret et al [2015] reported two adolescents with Phelan-McDermid syndrome and ASD resulting from pathogenic variants in SHANK3. The individuals presented with catatonia, regression, and behavioral issues after stressful events. Lithium reversed the regression and improved the behavioral issues, and the individuals returned to their pre-catatonia level of functioning. Egger et al [2017] described an adult with a SHANK3 pathogenic variant who had an atypical bipolar mood disorder that was stabilized by lithium treatment.

IGF-1. Insulin-like growth factor-1 (IGF-1) was investigated in a placebo-controlled, double-blind, crossover study involving nine children with Phelan-McDermid syndrome [Kolevzon et al 2014b]. Results indicated a significant improvement in social impairment and in restrictive behavior during the IGF-1 phase compared to the placebo phase. Nonetheless, this was a very small study and larger studies are required to confirm the validity of IGF-1 therapy.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Phelan-McDermid syndrome, caused by a deletion at chromosome 22q13.3 that includes at least part of SHANK3 or, more rarely, an intragenic SHANK3 pathogenic variant, is inherited in an autosomal dominant manner; however, the majority of affected individuals represent simplex cases (i.e., a single affected family member).

Risk to Family Members

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having a child with Phelan-McDermid syndrome. Note: If a parent is known to have a balanced chromosome rearrangement, genetic counseling should also address reproductive risks associated with balanced chromosome rearrangements.

Prenatal Testing and Preimplantation Genetic Testing

Pregnancies known to be at increased risk for Phelan-McDermid syndrome. Once a SHANK3 pathogenic variant or a 22q13.3 deletion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Prenatal testing to detect the SHANK3 pathogenic variant identified in the proband or CMA that will detect the 22q13.3 deletion found in the proband may be offered in the following instances:

• The parents do not have a SHANK3 pathogenic variant, 22q13.3 deletion, or balanced chromosome rearrangement but have had an affected child. In this instance, the recurrence risk associated with the possibility of parental germline mosaicism or other predisposing genetic mechanisms is approximately 1%.
• A parent has a balanced chromosome rearrangement that resulted in a previous child with a 22q13.3 deletion. Note: In most cases, the unbalanced rearrangement can be detected by CMA and this is the appropriate test to offer. In some cases, the parents may be concerned about producing a child with a balanced karyotype that would not be detected by CMA but would be seen by chromosome analysis and FISH. In all cases, genetic counseling is necessary to determine the priorities of the parents.

Both mosaic and non-mosaic deletions of 22q13.3 have been successfully identified prenatally [Riegel et al 2000, Phelan 2001, Maitz et al 2008, Koç et al 2009].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Pregnancies not known to be at increased risk for Phelan-McDermid syndrome. CMA performed in a pregnancy not known to be at increased risk may detect a 22q13.3 deletion.

Note: Regardless of whether a pregnancy is known or not known to be at increased risk for 22q13.3 deletion, prenatal test results cannot reliably predict the phenotype.

Molecular Pathogenesis

The size of the 22q13.3 deletion in Phelan-McDermid syndrome ranges from <50 kb to >9 Mb.

The majority of terminal deletions of 22q13.3 (69%-74%) occur on the paternal chromosome 22 [Luciani et al 2003, Wilson et al 2003].

The gene included in the critical region is SHANK3, near the q-terminus on chromosome 22. SHANK3 (previously known as PROSAP2) is completely or partially deleted in virtually all cases; rarely, it is disrupted by an apparently balanced translocation [Bonaglia et al 2001].

Molecular characterization of terminal deletions in three unrelated individuals with Phelan-McDermid syndrome identified the same 15-base pair repeat unit in the D22S167 sequence variant between exons 8 and 9 as a recurrent breakpoint [Wong et al 1997, Anderlid et al 2002, Bonaglia et al 2006].

Heterozygous inactivation of SHANK3 is responsible for the majority of neurologic features of Phelan-McDermid syndrome [Wilson et al 2003]. Analysis of deletion breakpoints in SHANK3 suggests the presence of a deletion hot spot [Bonaglia et al 2006].

Evidence for a role for SHANK3 in Phelan-McDermid syndrome:

• Bonaglia et al [2001] reported a child with a de novo balanced translocation t(12;22) (q24.1;q13.3) that disrupted SHANK3.
• Anderlid et al [2002] described the disruption of SHANK3 resulting from a 100-kb deletion in an individual with the Phelan-McDermid syndrome phenotype.
• In a study of two unrelated individuals with 100-kb deletions of 22q13, one of whom was the individual described by Anderlid et al [2002], Bonaglia et al [2006] concluded that the direct repeat within SHANK3 may form slipped (hairpin) structures with a strong potential for forming tetraplexes, suggesting a possible mechanism for the occurrence of a common breakpoint.
• Two studies, one involving 56 individuals with 22q13.3 deletion [Wilson et al 2003] and the other 32 individuals [Luciani et al 2003], proposed SHANK3 as a candidate gene for the neurologic deficits of Phelan-McDermid syndrome (developmental delay and impaired speech) because it is located in the critical region, is preferentially expressed in the cerebral cortex and the cerebellum, and encodes a protein in the postsynaptic density (PSD) of the excitatory synapses.
• Thirty-four of 35 individuals in a study of ring 22 were hemizygous for SHANK3 and demonstrated typical features of Phelan-McDermid syndrome including moderate to profound developmental delay, absent or delayed speech, autistic traits, and variable dysmorphic features. The single individual whose ring chromosome did not disrupt SHANK3 was a phenotypically normal female. This study lends further credence to the role of SHANK3 in normal neurologic development and supports the observation that hemizygosity for SHANK3 leads to intellectual disability, language deficits, and atypical behavior [Jeffries et al 2005].

Boccuto [personal observation] examined SHANK3 in 44 individuals with clinical features of Phelan-McDermid syndrome but with no apparent deletion of chromosome 22 by CMA, subtelomere FISH, or MPLA. Two loss-of-function variants were identified: c.3931delG (p.Glu1311fs) and a partial-gene deletion (detected by customized FISH using cosmids n66c4 and n85a3).

Together these data provide compelling evidence that SHANK3 is the gene responsible for at least the developmental delay and speech deficit associated with Phelan-McDermid syndrome. The contribution of epigenetic factors to the phenotypic expression in Phelan-McDermid syndrome is yet unknown.

In addition to deletion/disruption of SHANK3, deletion/disruption of other nearby genes as a cause of Phelan-McDermid syndrome seems possible. MAPK8IP2 is approximately 70 kb proximal to SHANK3 and is deleted in the majority of individuals with Phelan-McDermid syndrome [Giza et al 2010]. Experiments in mice demonstrate that Mapk8ip2 is highly expressed in the brain and is an essential component of the postsynaptic density. Mice lacking Mapk8ip2 demonstrate cognitive deficits reminiscent of those in individuals with deletion of 22q13.

Wilson et al [2008] reported two unrelated children with interstitial deletions of 22q13 proximal to, but not overlapping, SHANK3. The children had intellectual disability, severe language delay, hypotonia, and advanced height. The mother of one of the children who had the same deletion as her affected child had mild speech delay.

The potential contribution of genes other than SHANK3 to the phenotype of Phelan-McDermid syndrome has been suggested [Aldinger et al 2013, Sarasua et al 2014b, Oberman et al 2015, Tabet et al 2017, Mitz et al 2018]. The collective evidence suggests a potential role of genes more proximal than SHANK3 in the observed clinical variability of this condition.

Gene structure. SHANK3 encodes 22 canonic exons plus three alternatively spliced exons that are expressed only in tissue-specific isoforms. The longest isoform produces a mRNA transcript of 7,031 nucleotides (NM_033517.1) and is expressed exclusively in brain and testes. Gene expression and function is regulated by both alternative splicing of three variable exons and methylation of four intragenic promoters, which control the transcription of tissue- and time-specific isoforms [Maunakea et al 2010].

Pathogenic variants. Although the majority of Phelan-McDermid syndrome-associated variants are whole-gene deletions, a limited number of splice site, missense, nonsense, and frameshift variants have been reported. Most individuals with SHANK3 intragenic variants are described as having autism or intellectual disability [Boccuto et al 2013, Soorya et al 2013, Leblond et al 2014, Oberman et al 2015].

Normal gene product. The product of the main mRNA isoform of this gene, SH3 and multiple ankyrin repeat domains protein 3 (Shank3), is composed of 1,730 amino acids and belongs to a family of proteins that interact with receptors of the postsynaptic membrane. These multidomain proteins are important scaffolding molecules in the postsynaptic density (PSD) and function to receive and integrate synaptic signals and transduce them into postsynaptic cells. In addition to their role in the assembly of the PSD during synaptogenesis, the Shank proteins may play a role in synaptic plasticity and in the regulation of dendritic spine morphology [Boeckers et al 2002].

Abnormal gene product. Loss-of-function variants or chromosome rearrangements encompassing or disrupting SHANK3 cause haploinsufficiency of the gene, leading to destabilization of the PSD due to lack of Shank3 protein. In addition, pathogenic missense variants supposedly affecting the interaction of Shank3 with other PSD proteins result in a destabilizing effect.

Acknowledgments

The authors gratefully acknowledge the members of the Phelan-McDermid Syndrome Foundation for their participation in research and for their generous sharing of information.

Revision History

• 7 June 2018 (ha) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 25 October 2007 (me) Comprehensive update posted live
• 11 May 2005 (me) Review posted live
• 22 November 2004 (kp) Original submission

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