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Table 2 Main clinical features of individuals with SHANK3 mutations

From: Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations

  S1 S2 S3 S4 S5a S6 S7 S8 S9a S10 S11 S12 S13 S14 B1 B2b B3b Total (%)
Gender M M M F F M F M M M F F M M F F F 9 M, 8 F
Gestational age (wks) 36 39 40 Term 38 Term 33 40 39 Term 36.5 Term 40 41 40 36 36  
Birth weight (g) 2863 3400 3657 4000 3175 2948 1940 4111 4630 3230 3000 3728 2700 3090 2438 2551 2523  
Birth length (cm) 47 55 NK 53 NK 50 46 58 55 50 53 NK 48 51 48 NK NK  
Postnatal growth          
 Age at examination (y) 12 5 7 3 9 5 7 9 12 9 6 42 15 4 14 14 14 3–42
 Height (cm, percentile) 131 (< 1) 110 (27) 108 (< 1) 103 (93) NK 109 (50) 125 (45) 148 (95) 142 (17) 135 (56) 111 (4) 170 (85) 149 (< 1) 97 (4) 151 (25–50) 145 (< 1) 145 (< 1) 5/16 (31%) short
 Weight (kg, percentile) 32.6 (11) 20 (53) 18.8 (5) 17.2 (88) NK 17.3 (50) 35 (96) 36 (78) 29.5 (3) 29.5 (55) 18.2 (7) 69.4 (82) 48.1 (18) 15.4 (19) 55.1 (75) 59.1 (75) 40.5 (12)  
 OFC (cm, percentile) 56 (95) 50.8 (36) 52.7 (70) 50 (75) NK NK 51.2 (40) 54 (82) NK 53 (64) 50.5 (27) 57 (99) 54.5 (40) 46 (< 1) 52.7 (30) 57 (98) 57 (98) 3/14 (21%) macrocephaly; 1 (7%) microcephaly
Psychomotor development
 Sat independently (mo) 12 5–6 9–10 6 12 9 8–11 6 8–9 6 Normal 8 NK 5 8 6 6  
 Walked independently (mo) 24 16 14 15 16 14 18 14 14–15 12 24 20 14 13 14 19 19  
 First words and current language ability 3 y; now non-verbal No speech; vowel sounds and sounds of pleasure present No speech; previously had 10 signs but regressed to 3–4, babbling present, apraxic No speech; uses about 5 signs with word approximations Non-verbal 36 mo; 2-word phrases at 3.5 y; primarily single words with some phrase speech, stereotyped speech and echolalia 14 mo; first phrases at 24 mo, verbally fluent, complex speech 15 mo; never developed 2-word phrases, eventually lost all words Non-verbal 8 mo; 2-word phrases by 24 mo, now verbally fluent 4 y; had approximately 10 words; currently uses no words 15 mo; phrase speech at 3 y; was verbally fluent until 12–13 y but currently uses no words 10–15 words by 18 mo; understands roughly 40 signs; comprehension and expressive language is limited 10 mo; uses a few word approximations, some signs, apraxic At 3 y had approximately 200 words but only used 50 routinely; can speak in 2–3 word sentences but mostly echolalia 19 mo; combined words at 3.5 y; currently speaks in full sentences but developed word finding difficulties 19 mo; combined words at 3.5 y; spoke in full sentences but regressed at 9 y to only say 2–3 words, regained some vocabulary but fluctuating language Currently non-verbal 9/17 (53%), fluent speech 3/17 (18%)
 Intellectual disability (IQ or DQ) Profound ID (Mullen: DQ 6.7, NVDQ 10.3, VDQ 3.1) Profound ID (Mullen: DQ 21.3, NVDQ 30.1, VDQ 12.5) Profound ID (Mullen: DQ 14.7, NVDQ 18.8, VDQ 10.6) Profound ID (Mullen: DQ 16.5, NVDQ 19.5, VDQ 13.4) ID (no testing available) Severe ID (Mullen: CSS < 49, DQ 30.4, NVDQ 35, VDQ 25.8) Mild ID (DAS-II: GCA 50, Verbal 52, NV reasoning 74, spatial 32, special NV 49) Profound ID (Mullen: DQ 11.5, NVDQ 14.5, VDQ 8.5) Severe ID (no testing available) Mild ID (Stanford Binet: FSIQ 56, NVIQ 60, VIQ 56) Profound ID (Mullen: DQ 10.5, NVDQ 13.2, VDQ 7.9) Profound ID (Mullen: DQ 0.63, NVDQ 0.97, VDQ 0.29) Profound ID (Mullen: DQ 10.4, NVDQ 15.5, VDQ 5.2) Severe ID (Mullen: CSS < 49, DQ 26.4, NVDQ 33, VDQ 19.8) Mild ID (BDI at 4 y: adaptive SS 65, cognitive 65, communication 65, fine motor 72, gross motor 69, social 65) Mild ID (no testing available) Mild ID (no testing available) 17/17 (100%)
 Feeding difficulties + (chewing problems) − + (regurgitation, oral motor dysfunction, difficulty consuming solid foods, PEG tube) + (oral motor dysfunction since birth, dysphagia, drooling, overeating, chewing problems) + (failure to thrive, g-tube) − − (drooling) + (dysphagia, drooling, may induce vomiting when over-eats) + (difficulty chewing, dysphagia) + (history of oral motor dysfunction, drooling) + (history of dysphagia) + (drooling, dysphagia) + (difficulty latching, currently gagging and choking behaviors, dysphagia, drooling) + (oral motor dysfunction) − + (difficulty latching) + (difficulty latching) 13/17 (76%)
 Hypotonia + + + + + + + + + + + + + + − + + 16/17 (94%)
 Gait abnormalities + (apraxic, hypotonic, toe-walking) + (toe-walking, unsteady, needs assistance) + + + (slow pace) + (toe walking) + (mildly hypotonic) + + + + (apraxia) + (slow, hesitant and apraxic; previously reported as wide-based gait) + (mild but went through 6-month period in early childhood when he was unable to ambulate due to muscle weakness) + − − − 14/17 (82%)
Behavioral abnormalities
 ASD + + − + + + − + + − + NK + + + − − 11/16 (69%)
 Hyperactivity + + + + + + + − + + + − − − + − − 11/17 (65%)
 Aggression − − + − − − + − − + + + + − − + + 8/17 (47%)
 Self-injury − − + − − − − + − − − + − − − NK NK 3/15 (20%)
 Sleep disturbance − + + + + − − − + − + + + + + − − 10/17 (59%)
 Pica + + + + + + − + + − − − − − − − − 8/17 (47%)
 Repetitive behaviors (type) + (stereotypic motor movements in upper and lower extremities, forced exhalations) + (spinning, hand-flapping, teeth grinding) + (repetitive motor mannerisms, stereotypic vocalizations) + (bouncing, tapping, upper extremity motor stereotypies) + (chewing, teeth grinding, breath holding) + (chewing, teeth grinding, hand flapping, stereotypic vocalizations) + (self-stimulation, insistence on routines) + (hand-flapping, chewing) + (hand-flapping) + (restricted interests, perseveration) + (teeth grinding, repeatedly taps objects, walks in circles) + (pacing, upper extremity motor stereotypies) + (hand flapping, chewing, stereotypic vocalizations, teeth grinding) + (chewing, hand flapping, repetitive jumping, stereotypic vocalizations) + (finger and toe tapping) − + (chewing, tapping teeth with finger) 16/17 (94%)
 Psychosis − − − − − − − − − − − + (12–13 y) − − − − − 1/17 (6%)
 Regression (age and details) + (5 y; some language loss) − + (6 y; motor regression and lost some sign language, at one point stopped walking for 6 weeks, slowly regained ambulatory skills; at 5 y, some language loss) + (15 mo; stopped babbling, loses motor skills when sick) − − − + (3.5 y; language and motor skills, stopped walking, socially withdrawn and less responsive) + (3–4 y; loss of fine motor skills) − + (4.5 y; loss of language and motor skills, lost ability to ambulate and eye contact, lethargic, developed unusual motor stereotypies, regression coincided with diagnosis of parasitic infection) + (12–13 y; intermittent periods of behavioral, motor, and language regressions sometimes preceded by viral infection, included psychiatric symptoms. Currently non-verbal and unable to walk unsupported) + (2 y; lost all words, 7 y; regression in handwriting [can no longer hold a pen], motor regression began roughly around when seizures started) + (12–18 mo; loss of babbling, loss of few words, eye contact, and gesturing to request) − + (13 y; “manic-like” behavior) + (9–10 y; “manic-like” behavior) 11/17 (65%)
Neurological findings
 Brain MRI (age) Diffuse ventricular enlargement, colpocephaly, communicating hydrocephalus, thinning of parieto-occipital white matter and corpus callosum (8 y) No MRI Leukodystrophy (5 y) Grossly normal but scattered areas of subtle FLAIR hyperintensity (2 y) NK Grossly normal but hyper-intensity in the left inferior parietal subcortical white matter possibly related to gliosis (4 y) Normal (5 y) Normal (3 y) Normal (5, 9, and 11 y) Normal (7 y) Normal (4.5 y) Normal (14 and 18 y) Venous angioma (6 y); normal (16 y) Normal (3 y) Bilateral T2 hyper-intensities of posterior centrum semiovale (12 y) Mild cerebellar tonsillar ectopia (14 y) Normal (14 y) Abnormal in 5/15 (33%)
 Seizures (age of onset, type) − − + (5 y, Landau-Kleffner variant; 6 y epileptic encephalopathy) − − − − − − (10 y, suspected complex partial seizures) − − − + (3 y febrile; 6 y focal; 15 y began 1–10 absence or partial seizures daily) + (4 y, generalized myoclonic seizures) − + (14 y, atypical absence) + (7 y, atypical absence and tonic) 5/17 (29%)
 Abnormal EEG − − + (localized sleep potentiated epileptiform discharges mainly in the midline and central regions during slow wave sleep) + (increased theta wave activity; bilateral K-complexes, and spindles and vertex waves during sleep. Left frontal spike and wave activity) + (spikes) + (spike and wave activity in frontotemporal lobes; no seizures) − − + (right frontal lobe spikes, slowing) − + (left frontal spikes/polyspikes, intermittent polymorphic slowing [L>R] in the temporal region, and background slowing during sleep) − + (high-voltage spike and sharp activity in frontal regions) + (occasional generalized polyspikes or polyspike-wave with shifting hemispheric predominance during sleep) − + (no occipital dominant rhythm) − 9/17 (53%)
Gastrointestinal problems
 Gastroesophageal reflux − + + − − − − + + − − + − − − − − 5/17 (29%)
 Constipation + − + + + + − − + − − + + − + − − 9/17 (53%)
 Diarrhea − − + − + − − + − − + − + − − − − 5/17 (29%)
Additional features
 Increased pain tolerance + + + + + − + + + + + + + + + + + 16/17 (94%)
 Decreased perspiration/heat intolerance − − + NK − NK − NK + − − NK − NK − − − 2/12 (17%)
 Recurrent infections − + (otitis, MT) + (otitis) − − + (otitis, upper respiratory tract) − + (otitis, MT) − + (otitis, tonsillitis) + (otitis, MT; yeast) + (otitis, bronchitis) + (otitis, sinusitis) + (otitis, MT) − − − 9/17 (53%)
 Visual problems − + (strabismus, corrective surgery) + (mild hyperopic astigmatism) − − + (strabismus) − − − − − − − − − + (myopia) + (myopia) 5/17 (29%)
 Congenital heart defect − − − − − − + (coronary artery fistula) − − − − − − − − − − 1/17 (6%)
 Renal abnormalities − −c − − − − −c − − − − − −c −c −c −c − 0/17
 Allergies + (penicillin) + (food, seasonal) − − + (food) + (penicillin, seasonal) + (seasonal) + (food) + (seasonal) + (penicillin) + (seasonal) + (food, dust, pets) + (food) + (food) − − − 12/17 (71%)
 Asthma − − − − − + + (allergy induced) − − − − − − + − − − 3/17 (18%)
 Eczema − + − − − − − + + + − − + + − − − 6/17 (35%)
 Other        Birth by in vitro fertilization   Sleep apnea    Sleep apnea, atrial fibrillation, intermittent hypoglycemia    Left preauricular skin tag, scoliosis Episode of idiopathic intracranial hypertension at 12 y   
  1. + present, − absent, ASD autism spectrum disorder, BDI Battelle Developmental Inventory, CSS Composite Standard Score, DAS-II Differential Ability Scales, Second Edition, DQ developmental quotient, EEG electroencephalography, F female, FSIQ full scale intelligence quotient, GCA general conceptual ability, ID intellectual disability, M male, MRI magnetic resonance imaging, MT myringotomy tubes, NA not applicable, NK not known, NV non-verbal, NVDQ non-verbal developmental quotient, NVIQ non-verbal intelligence quotient, PEG percutaneous endoscopic gastrostomy, SS standard score, VDQ verbal developmental quotient, VIQ verbal intelligence quotient
  2. aIndividuals not directly evaluated
  3. bMonozygotic twins
  4. cNormal renal evaluation (ultrasound or computed tomography)
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Molecular Autism

ISSN: 2040-2392