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Table 2 Main clinical features of individuals with SHANK3 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 | |||||||||||||
