Phelan-Mcdermid Syndrome

A number sign (#) is used with this entry because Phelan-McDermid syndrome (PHMDS) can be caused by a heterozygous contiguous gene deletion at chromosome 22q13 or by mutation in the SHANK3 gene (606230), which is located within the minimum critical region.

Description

Phelan-McDermid syndrome is a developmental disorder with variable features. Common features include neonatal hypotonia, global developmental delay, normal to accelerated growth, absent to severely delayed speech, autistic behavior (see 209850), and minor dysmorphic features (Precht et al., 1998; Prasad et al., 2000; Durand et al., 2007).

Clinical Features

Phelan et al. (2001) compared the phenotypes of 37 patients with 22q13 deletion syndrome with those of 24 published cases. All 37 patients presented with global developmental delay and absent or severely delayed expressive speech. Hypotonia was present in 97% of patients, and 95% showed normal to accelerated growth. Other less common features associated with this syndrome included increased tolerance to pain, dysplastic toenails, chewing behavior, fleshy hands, dysplastic ears, pointed chin, dolichocephaly, ptosis, tendency to overheat, and epicanthic folds.

Bonaglia et al. (2001) studied a 4.5-year-old boy with all the features of terminal 22q13.3 deletion syndrome. He had only slight delay in early motor milestones and severely compromised language development, in that he was unable to utter single words until he was 2 years old. At age 4.5 years, his verbal expression was limited to a few words. The boy had mild mental retardation (overall IQ of 54) and sharply limited verbal abilities (verbal IQ of 32 and performance IQ of 70). Neurologic examination showed mild hypotonia and minor dysmorphic features (dolichocephaly, epicanthic folds, and saddle nose with bulbous tip).

Wilson et al. (2003) noted that very few organ malformations had been reported in patients with 22q13 deletion syndrome.

Lindquist et al. (2005) reported the clinical features of 6 cases of 22q13 deletion in Denmark. Consistent phenotypic features were generalized developmental delay, hypotonia, compromised language development, normal or accelerated growth, and minor facial dysmorphisms. Other features included partial absence of corpus callosum, bilateral ureteropelvic structure, gastroesophageal reflux, and hearing loss.

Tabolacci et al. (2005) reported 2 brothers, born of nonconsanguineous parents, with features suggestive of Clark-Baraitser syndrome (300602). FISH screening revealed a cryptic subtelomeric deletion of chromosome region 22q13, and segregation analysis revealed the deletion to be of maternal origin, mostly likely due to germinal mosaicism. Tabolacci et al. (2005) suggested that patients diagnosed with Clark-Baraitser syndrome be tested for submicroscopic 22qter deletion.

Soorya et al. (2013) reported a serially ascertained sample of 32 patients with SHANK3 deletion or mutation who were evaluated by a team of child psychiatrists, neurologists, clinical geneticists, molecular geneticists, and psychologists. Patients were evaluated for autism spectrum disorder using the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule-G (ADOS-G). Thirty participants had 22q13.3 deletions ranging from 101 kb to 8.45 Mb, and 2 participants had de novo SHANK3 point mutations. The sample was characterized by high rates of autism spectrum disorder: 27 (84%) met criteria for autism spectrum disorder and 24 (75%) for autistic disorder. Most patients (77%) exhibited severe to profound intellectual disability, and only 5 (19%) used some words spontaneously to communicate. Dysmorphic features, hypotonia, gait disturbance, recurring upper respiratory tract infections, gastroesophageal reflux, and seizures were also common. Larger deletions were associated with increased levels of dysmorphic features, medical comorbidities, and social communication impairments related to autism. Analyses of individuals with small deletions or point mutations identified features related to SHANK3 haploinsufficiency, including ASD, seizures and abnormal EEG, hypotonia, sleep disturbances, abnormal brain MRI, gastroesophageal reflux, and certain dysmorphic features. In this study of 32 patients, 53% had large, fleshy hands; 47% had a bulbous nose; 44% had long eyelashes; 41% had ear anomalies; 34% had hypoplastic or dysplastic toenails; 31% had full lips, epicanthal folds, or macrocephaly; 25% had dolichocephaly, high arched palate, hyperextensibility, full cheeks, or periorbital fullness; and 22% had a pointed chin or abnormal spinal curvature. A smaller minority had other dysmorphic features. In terms of medical comorbidities, 88% had increased pain tolerance; 75% had hypotonia; 53% had recurring upper respiratory tract infections; 44% had gastroesophageal reflux; 41% had sleep disturbances or either febrile or nonfebrile seizures; and 38% had constipation and/or diarrhea or renal abnormalities. A smaller minority had other comorbidities.

Disciglio et al. (2014) reported 9 patients with features of Phelan-McDermid syndrome associated with interstitial deletions of chromosome 22q13 that did not include the SHANK3 gene. Clinical features included developmental delay, speech delay, hypotonia, and feeding difficulties. In addition, the majority of patients had macrocephaly.

Other Features

Sathyamoorthi et al. (2009) reported a patient with Phelan-McDermid syndrome and atypical teratoid/rhabdoid tumor. The girl presented at age 13 months with a history of torticollis, plagiocephaly, hypotonia, hydronephrosis, and strabismus. Examination revealed large ears, circumferential skin creases in arms and legs, inverted nipples, mild lipomastia, a deep sacrococcygeal crease, overriding second toes, long middle toes, upturned toenails on second and fourth toes, and atrophic toenails on fifth toes, as well as increased secondary creases in both soles and disruption of the vertical palmar flexion creases. Array CGH analysis revealed a de novo subtelomeric 7.2-Mb deletion of chromosome 22q13.2-q13.33. At 23 months of age, the patient presented with headache, irritability, and persistent vomiting, and MRI showed a 2.5-cm enhancing mass in the fourth ventricle; postoperative histopathologic diagnosis was atypical teratoid/rhabdoid tumor and the patient died at 26 months of age. A somatic frameshift mutation in the INI1 gene (601607) on chromosome 22q11.2 was identified in tumor tissue.

Tufano et al. (2009) reported a 7-year-old Italian girl with chromosome 22q13 deletion syndrome associated with fulminant autoimmune hepatitis requiring liver transplantation. Bartsch et al. (2010) noted that the patient reported by Tufano et al. (2009) had recurrence of autoimmune hepatitis that was managed with immunosuppression. Array CGH analysis found a 1.535-Mb deletion of chromosome 22q13.32-qter, including approximately 39 genes. Bartsch et al. (2010) reported another girl, who was of German descent, with chromosome 22q13.3 deletion syndrome and fulminant hepatic failure, most likely caused by hyperacute autoimmune hepatitis triggered by a viral infection. Emergency liver transplantation was required. This 4-year-old girl had severe developmental delay and absent speech, but showed developmental catch-up following the liver transplantation, possibly suggesting that chronic hepatic disease could contribute to developmental delay in a subset of these patients. Array CGH analysis identified a 5.675-Mb terminal deletion of 22q13.31-qter, which included approximately 55 genes. The deletion overlap comprises the C-terminal 1.535 Mb of 22q13.3 and contained candidate genes for fulminant hepatic failure including PIM3 (610580) and SHANK3. Bartsch et al. (2010) recommended liver function tests and array CGH testing in the management of patients with this disorder, since affected individuals may have a predisposition to the development of autoimmune hepatitis.

Shcheglovitov et al. (2013) generated induced pluripotent stem (iPS) cells from individuals with Phelan-McDermid syndrome and autism and used them to produce functional neurons. Shcheglovitov et al. (2013) showed that Phelan-McDermid syndrome neurons have reduced SHANK3 expression and major defects in excitatory, but not inhibitory, synaptic transmission. Excitatory synaptic transmission in Phelan-McDermid syndrome neurons could be corrected by restoring SHANK3 expression or by treating neurons with insulin-like growth factor-1 (IGF1; 147440). IGF1 treatment promoted formation of mature excitatory synapses that lack SHANK3 but contained PSD95 (602887) and NMDA receptors (see 138249) with fast deactivation kinetics. Shcheglovitov et al. (2013) concluded that their findings provided direct evidence for a disruption in the ratio of cellular excitation and inhibition in Phelan-McDermid syndrome neurons, and pointed to a molecular pathway that can be recruited to restore it.

Cytogenetics

Flint et al. (1995) described a 12-year-old boy with delayed expressive speech, mild mental retardation, normal facial features, and a negative family history for mental retardation. Although his high-resolution karyotype was normal, the paternal allele of the minisatellite probe D22S163 was found to be deleted; other 22q13.3 probes were present in 2 copies, indicating that the patient carried a microdeletion spanning the terminal 130 kb of 22q.

Wong et al. (1997) analyzed the 130-kb deletion identified by Flint et al. (1995) and determined that the breakpoint was within the D22S163 locus. Estimating that the distal 60 kb of the deletion would be rich in subtelomeric repeats, the authors concluded that only the proximal 70 kb might contain genes.

The patient reported by Bonaglia et al. (2001) showed a de novo balanced translocation between chromosomes 12 and 22, t(12;22)(q24.1;q13.3). FISH investigation showed that the translocation was reciprocal. Further studies located the chromosome 12 breakpoint in an intron of the FLJ10659 gene (606231) and the chromosome 22 breakpoint within exon 21 of the PSAP2 (SHANK3) gene. Short homologous sequences were found at the breakpoint on both derivative chromosomes. The authors proposed that disruption of the SHANK3 gene was likely to be responsible for the clinical disorder.

In a 33-year-old woman with a submicroscopic 22q13 deletion, mild mental retardation, speech delay, autistic symptoms, and mild facial dysmorphism, Anderlid et al. (2002) performed FISH mapping and determined that the approximately 100-kb deletion completely encompassed the ACR (102480) and RABL2B (605413) genes and disrupted SHANK3.

Luciani et al. (2003) reported cytogenetic, molecular, and clinical analyses of 32 cases of telomeric 22q13 deletions resulting from rings, simple deletions, and translocations. The deletions were extremely variable in size, extending from 160 kb to 9 Mb. Their parental origin was much more often paternal (74%) than maternal (26%). Luciani et al. (2003) pointed out that the minimal critical region responsible for the monosomy 22q13 phenotype included the genes SHANK3, ACR (102480), and RABL2B (605413), but not ARSA (607574).

Of 6 cases of 22q13 deletion in Denmark, Lindquist et al. (2005) found that 4 had a simple deletion, 1 had a mosaic deletion, and 1 had a deletion and a duplication. The deletions ranged from 4 to 9 Mb.

To investigate large copy number variants (CNVs) segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence to support the association of deletion at chromosome 22q13 with autism (CNV P = 0.090). They identified 4 deletions in this region; all of these were disease-associated.

Sarasua et al. (2014) used customized oligoarray CGH of 22q12.3-qter to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. Specific genomic regions and candidate genes within 22q13.2-q13.32 were associated with 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.

Disciglio et al. (2014) reported 9 patients with intellectual disability and a phenotype consistent with PMS who had heterozygous interstitial deletions of chromosome 22q13 ranging from 2.7 Mb to 6.9 Mb and not involving the SHANK3 gene. The size of the minimally deleted region was about 950 kb and included 12 genes, including SULT4A1 (608359) and PARVB (608121), which Disciglio et al. (2014) suggested could be associated with neurologic features and macrocephaly/hypotonia, respectively. This study suggested that haploinsufficiency of genes besides SHANK3 in the 22q13 region contributes to cognitive and speech development.

Molecular Genetics

Bonaglia et al. (2006) studied 2 patients, 1 previously reported by Anderlid et al. (2002), with cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100 kb of chromosome 22q13.3. Both patients showed a breakpoint within the same 15-bp repeat unit, overlapping results obtained by Wong et al. (1997) and suggesting that a recurrent deletion breakpoint exists within the SHANK3 gene. Bonaglia et al. (2006) stated that this was the first instance of terminal deletions having a recurrent breakpoint, and noted that because the deletion partially overlaps the commercial subtelomeric probe, FISH results are difficult to interpret and similar cases may be overlooked.

Durand et al. (2007) reported evidence showing that abnormal gene dosage of SHANK3 is associated with severe cognitive deficits, including language and speech disorder and autism spectrum disorder. They reported 3 families with autism spectrum disorder and unambiguous alteration of 22q13 or SHANK3. In the first family, the proband with autism, absent language, and moderate mental retardation carried a de novo deletion of 22q13. The deletion breakpoint was located in intron 8 of SHANK3 and removed 142 kb of the terminal 22q13. In a second family, 2 brothers with severely impaired speech, severe mental retardation, and a diagnosis of autism had a heterozygous 1-bp insertion in the SHANK3 gene (606230.0001), resulting in a truncated protein. The mutation was absent in an unaffected brother and in the unaffected parents. In a third family studied by Durand et al. (2007), a terminal 22q deletion was found in a girl with autism and severe language delay, and a 22qter partial trisomy in her brother with Asperger syndrome who demonstrated precocious language development and fluent speech. These unbalanced cytogenetic abnormalities were inherited from a paternal translocation, t(14;22)(p11.2;q13.33). Studies with informative SNPs and quantitative PCR permitted mapping of the breakpoint on 22q13 between ALG12 (607144) and MLC1 (605908). The deletion and duplication rearrangement observed in both sibs involved 25 genes, including SHANK3, located in the 800-kb terminal segment of 22q13. Durand et al. (2007) concluded that gene dosage of SHANK3 is important for speech and language development as well as social communication.

Moessner et al. (2007) identified deletions in the SHANK3 gene on chromosome 22q13 in 3 (0.75%) of 400 unrelated patients with an autism spectrum disorder. The deletions ranged in size from 277 kb to 4.36 Mb; 1 patient also had a 1.4-Mb duplication at chromosome 20q13.33. The patients were essentially nonverbal and showed poor social interactions and repetitive behaviors. Two had global developmental delay and mild dysmorphic features. A fourth patient with a de novo missense mutation in the SHANK3 gene had autism-like features but had diagnostic scores above the cutoff for autism; she was conceived by in vitro fertilization.

Dhar et al. (2010) carried out clinical and molecular characterization of 13 patients with varying sizes of deletion in the 22q13.3 region. Developmental delay and speech abnormalities were common to all and comparable in frequency and severity to previously reported cases. Array-based comparative genomic hybridization showed the deletions to vary from 95 kb to 8.5 Mb. Two patients had a smaller 95-kb terminal deletion with breakpoints within the SHANK3 gene while 3 other patients had a similar 5.5-Mb deletion, implying the recurrent nature of these deletions. The 2 largest deletions were found in patients with ring chromosome 22. No correlation could be made with deletion size and phenotype although complete/partial SHANK3 was deleted in all patients.

By specific screening of the SHANK3 gene in 221 patients with autism spectrum disorders, Boccuto et al. (2013) identified 5 (2.3%) index patients with heterozygous changes in that gene (see, e.g., 606230.0004-606230.0006). Most had some additional features including seizures, developmental delay, and mild facial dysmorphism. Screening of this gene in an independent cohort of 104 patients identified 1 (0.9%) with a SHANK3 missense mutation. No cell lines were available from the patients, so functional or expression studies could not be performed. Boccuto et al. (2013) also identified a c.1304+48C-T transition (rs76224556) in 17 (7.7%) cases, including 5 with autistic disorder and 12 with PDD-NOS. Four (23.5%) of these patients had an affected sib who also carried the variant. The variant was demonstrated to be inherited from an apparently unaffected parent in 15 cases. However, this variant was significantly more frequent in the patient cohort than in the combined control population (7.7% vs 1.4%, p value less than 0.0002). In the replication cohort, 8 (7.7%) of 104 patients carried the c.1304+48C-T variant. This change occurs in a highly CG-rich region and causes the loss of a CpG dinucleotide, which may affect methylation status. Boccuto et al. (2013) concluded that variation in the SHANK3 gene increases the basal susceptibility to autism spectrum disorders, which have a complex etiology.

Genotype/Phenotype Correlations

In their study of 32 cases of telomeric 22q13 deletions resulting from rings, simple deletions, and translocations, Luciani et al. (2003) found no gross phenotypic differences between the 22q13 deletion and the ring 22 syndromes for similarly sized deletions. Nevertheless, behavioral disorders were a constant feature and increased in severity with age. Although patients with simple 22q13 terminal deletion had a general tendency to overgrowth, the patients with a ring 22 often showed growth failure.

Lindquist et al. (2005) reported that the clinical phenotype of 6 patients with 22q13 deletion in Denmark was similar, although some specific features might have been attributable to differences in deletions. The phenotype in the patient with a deletion and a duplication was different from that in the other 5 patients; he showed severe failure to thrive and growth failure as well as significantly dysmorphic facial features.

Wilson et al. (2003) determined the deletion size and parent of origin in 56 patients with the 22q13 deletion syndrome. Similar to other terminal deletion syndromes, there was an overabundance of paternal deletions. The deletions varied widely in size, from 130 kb to more than 9 Mb; however, all 45 patients who could specifically be tested for the terminal region containing the PSAP2 (SHANK3) gene showed a deletion of this gene. Comparison of clinical features to deletion size showed few correlations. Some measures of developmental assessment did correlate with deletion size; however, all patients showed some degree of mental retardation and severe delay or absence of expressive speech, regardless of deletion size. Because the SHANK3 gene encodes a structural protein of the postsynaptic density, the analysis supported haploinsufficiency of this gene as a major causative factor in the neurologic symptoms of 22q13 deletion syndrome.

Wilson et al. (2008) reported 2 unrelated patients with interstitial deletions of chromosome 22q13 that did not include the SHANK3 gene; both patients had 2 copies of SHANK3. The phenotype was similar to that observed in 22q13 deletion syndrome, including psychomotor retardation, hypotonia, speech delay, and overgrowth. One child was more severely affected; the second child was able to open a computer by himself and use a mouse, and he could feed and dress himself. Neither child had high pain tolerance, upper respiratory problems, or toenail abnormalities. The mother of the second child also carried the deletion; she had speech problems and was slow to walk, but attended normal school. Microsatellite and FISH analysis showed that both deletions were entirely contained within the largest terminal 22q13 deletion reported, but did not overlap with the 9 smallest deletions of 22q13 previously reported. Wilson et al. (2008) concluded that genes on chromosome 22q12 other than SHANK3 can have a major effect on cognitive and language development and noted the general nonspecificity of the phenotype.

Sarasua et al. (2011) used high-resolution oligonucleotide array CGH to delineate precisely the breakpoints in 71 patients with Phelan-McDermid syndrome who had a terminal deletion of chromosome 22q13. Patient deletion sizes were highly variable, ranging from 0.22 to 9.22 Mb, and there were no common breakpoints. SHANK3 was deleted in all cases, and MAPK8IP2 (607755) was deleted in all but 2 individuals. Larger deletions including regions proximal to SHANK3 were significantly associated with 16 features: neonatal hypotonia, neonatal hyporeflexia, neonatal feeding problems, speech/language delay, delayed age at crawling, delayed age at walking, severity of developmental delay, male genital anomalies, dysplastic toenails, large or fleshy hands, macrocephaly, tall stature, facial asymmetry, full brow, atypical reflexes, and dolichocephaly. Patients with autism spectrum disorders were found to have smaller deletion sizes (median of 3.39 Mb) than those without autism spectrum disorders, although this may have reflected difficulty in assessing autism in patients with severe developmental delay.