Background
Methods
Participants
Genetic testing
Review of previously reported SHANK3 mutations
Clinical evaluation
ASD phenotype
Intellectual functioning
Adaptive behavior
Language skills
Motor skills
Sensory processing
Results
SHANK3 mutations
ID | Coding DNA changea | Protein changeb | Genomic change (hg19) | Location | Effect | Inheritance | Variant classification [25] |
---|---|---|---|---|---|---|---|
S1c | c.1527G>A | p.Trp509* | chr22:g.51137146G>A | Exon 12 | Nonsense | De novo | Pathogenic |
S2 | c.2471delC | p.Pro824Argfs*69 | chr22:g.51158732delC | Exon 21 | Frameshift | De novo | Pathogenic |
S3d | c.2499delG | p.Pro834Argfs*59 | chr22:g.51158760delG | Exon 21 | Frameshift | De novo | Pathogenic |
S4 | c.2946_2949delCCGC | p.Arg983Serfs*94 | chr22:g.51159207_51159210delCCGC | Exon 21 | Frameshift | De novo | Pathogenic |
S5 | c.3095_3107delTGGGGGCCATCGA | p.Val1032Glyfs*42 | chr22:g.51159356_51159368delTGGGGGCCATCGA | Exon 21 | Frameshift | De novo | Pathogenic |
S6 | c.3424_3425delCT | p.Leu1142Valfs*153 | chr22:g.51159685_51159686delCT | Exon 21 | Frameshift | De novo | Pathogenic |
S7 | c.3679dupG | p.Ala1227Glyfs*69 | chr22:g.51159940dupG | Exon 21 | Frameshift | Non-paternal | Pathogenic |
S8 | c.3679dupG | p.Ala1227Glyfs*69 | chr22:g.51159940dupG | Exon 21 | Frameshift | De novo | Pathogenic |
B1e | c.3679dupG | p.Ala1227Glyfs*69 | chr22:g.51159940dupG | Exon 21 | Frameshift | De novo | Pathogenic |
S9 | c.3764_3776delGGGCCCAGCCCCC | p.Arg1255Leufs*25 | chr22:g.51160025_51160037delGGGCCCAGCCCCC | Exon 21 | Frameshift | De novo | Pathogenic |
B2, B3e,f | c.4065_4066delTG | p.Val1357Glyfs*4 | chr22:g.51160326_51160327delTG | Exon 21 | Frameshift | De novo | Pathogenic |
S10 | c.4229delC | p.Pro1410Hisfs*18 | chr22:g.51160490delC | Exon 21 | Frameshift | De novo | Pathogenic |
S11 | c.4577_4578delCC | p.Ala1526Glufs*16 | chr22:g.51160838_51160839delCC | Exon 22 | Frameshift | De novo | Pathogenic |
S12 | c.4906_4921dupTCCCCCTCGCCGTCGC | p.Pro1641Leufs*58 | chr22:g.51169450_51169465dupTCCCCCTCGCCGTCGC | Exon 22 | Frameshift | De novo | Pathogenic |
S13g | c.5008A>T | p.Lys1670* | chr22:g.51169552A>T | Exon 22 | Nonsense | Non-maternal | Likely pathogenic |
c.3872C>T | p.Ser1291Leu | chr22:g.51160133C>T | Exon 21 | Missense | Non-maternal | Likely benign | |
S14 | c.5014G>T | p.Asp1672Tyr | chr22:g.51169558G>T | Exon 22 | Missense | De novo | Likely pathogenic |
Clinical phenotype of SHANK3 haploinsufficiency
Phenotypic spectrum in the individuals from our cohort
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 |
S1a | S2 | S3 | S4 | S7 | S8 | S10 | S11 | S12 | S13 | S14 | Total (%) | |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Gender | M | M | M | F | F | M | M | F | F | M | M | 7 M, 4 F |
Age at examination (years) | 12 | 5 | 7 | 3 | 7 | 9 | 9 | 6 | 42 | 15 | 4 | 3–42 |
Craniofacial features | ||||||||||||
Microcephalyb | − | − | − | − | − | − | − | − | − | − | + | 1/11 (9%) |
Macrocephalyc | − | − | − | − | − | − | − | − | + | − | − | 1/11 (9%) |
Dolichocephaly | − | − | + | − | − | − | − | − | − | − | − | 1/11 (9%) |
Synophrys | − | − | − | − | − | − | − | − | − | − | − | 0 |
Sparse eyebrows | − | − | − | + | − | − | − | − | − | + | − | 2/11 (18%) |
Long eyelashes | + | + | − | + | + | + | − | + | + | + | − | 8/11 (73%) |
Periorbital fullness | + | + | − | + | − | − | − | − | − | + | − | 4/11 (36%) |
Deep set eyes | − | + | − | + | − | + | + | + | − | − | − | 5/11 (45%) |
Ptosis | − | − | − | − | − | − | − | − | − | − | − | 0 |
Epicanthal folds | + | + | − | + | − | − | + | − | − | − | + | 5/11 (45%) |
Hypertelorism | − | − | − | − | − | − | − | − | − | − | − | 0 |
Wide nasal bridge | + | + | − | + | + | + | − | − | − | − | + | 6/11 (55%) |
Bulbous nose | − | + | − | + | + | + | − | − | − | + | + | 6/11 (55%) |
Anteverted nares | − | − | − | − | + | − | − | − | − | − | − | 1/11 (9%) |
Full cheeks | − | − | − | + | − | − | − | − | − | + | − | 2/11 (18%) |
Malar hypoplasia | + | + | − | + | − | − | − | − | + | + | − | 5/11 (45%) |
Thin upper vermillion | − | + | + | − | − | − | − | + | − | − | − | 3/11 (27%) |
Thick lower vermillion | + | + | + | − | − | − | − | − | − | − | − | 3/11 (27%) |
Short philtrum | − | − | − | − | − | − | − | − | − | − | − | 0 |
Long philtrum | − | + | − | − | − | − | + | − | + | − | − | 3/11 (27%) |
Malocclusion | + | + | − | + | + | + | + | − | + | − | − | 7/11 (64%) |
High arched palate | + | + | − | + | − | − | + | − | NE | + | + | 6/10 (60%) |
Ear anomalies | − | − | − | + (low set ears) | − | − | + (overfolded helix) | − | + (fleshy ears) | − | + (prominent ears) | 4/11 (36%) |
Micrognathia | − | − | − | − | − | − | − | − | − | − | − | 0 |
Macrognathia | + | − | − | − | + | − | − | − | + | − | − | 3/11 (27%) |
Pointed chin | + | − | − | + | + | − | + | + | + | + | − | 7/11 (64%) |
Hand and feet anomalies | ||||||||||||
Large fleshy hands | − | − | − | + | − | − | − | − | − | + | + | 3/11 (27%) |
5th finger clinodactyly | + | + | − | + | + | + | + | − | + | + | + | 9/11 (82%) |
Partial syndactyly of toes 2–3 | − | + | − | + | − | − | + | − | − | + | + | 5/11 (45%) |
Sandal gap | + | + | + | NE | + | + | − | NE | − | + | − | 6/9 (67%) |
Hypoplasia of distal phalanges of 5th finger | − | − | − | − | − | − | − | − | + | + | − | 2/11 (18%) |
Ectodermal anomalies | ||||||||||||
Hypertrichosis | − | − | − | − | − | − | − | − | − | − | − | 0 |
Abnormal hair whorl | − | − | − | − | − | − | − | + | − | + | − | 2/11 (18%) |
Hypoplastic/dysplastic toenails | + | − | − | + | − | + | − | + | + | − | + | 6/11 (55%) |
Hypoplastic/dysplastic fingernails | + | + | − | − | − | − | − | − | − | − | − | 2/11 (18%) |
Other features | ||||||||||||
Short stature/delayed growthd | + | − | + | − | − | − | − | − | − | + | − | 3/11 (27%) |
Tall stature/accelerated growthe | − | − | − | − | − | − | − | − | − | − | − | 0 |
Hyperextensibility | − | − | − | + | + | + | + | − | NE | + | + | 6/10 (60%) |
Sacral dimple | − | − | NE | − | − | − | − | − | − | − | − | 0 |
Scoliosis | − | − | − | − | − | − | − | − | − | + | − | 1/11 (9%) |
Total dysmorphic features | 15 | 16 | 5 | 18 | 10 | 9 | 10 | 6 | 11 | 17 | 11 | 11/11 (100%) |
Clinical features | Individuals with SHANK3 mutations (current study) | Individuals with 22q13 deletions [2] |
---|---|---|
Intellectual disability | 17/17 (100%) | 29/30 (97%) |
ASD | 11/16 (69%) | 26/30 (87%) |
Verbally fluent | 3/17 (18%) | 0/30 |
Repetitive behaviors | 16/17 (94%) | 30/30 (100%) |
Hyperactivity | 11/17 (65%) | 14/30 (47%) |
Aggression | 8/17 (47%) | 13/30 (43%) |
Sleep disturbance | 10/17 (59%) | 12/30 (40%) |
Hypotonia | 16/17 (94%) | 23/30 (77%) |
Gait abnormalities | 14/17 (82%) | 13/14 (93%) |
Seizures | 5/17 (29%) | 12/30 (40%) |
Abnormal brain MRI | 5/15 (33%) | 18/26 (69%) |
Short staturea | 5/16 (31%) | 3/30 (10%) |
Tall statureb | 0/16 | 1/30 (3%) |
Microcephalyc | 1/14 (7%) | 2/30 (7%) |
Macrocephalyd | 3/14 (21%) | 9/30 (30%) |
Dolichocephaly | 1/11 (9%) | 7/30 (23%) |
Sparse hair/abnormal whorl | 2/11 (18%) | 5/30 (17%) |
Long eyelashes | 8/11 (73%) | 13/30 (43%) |
Periorbital fullness | 4/11 (36%) | 8/30 (27%) |
Hypertelorism | 0/11 | 3/30 (10%) |
Deep set eyes | 5/11 (45%) | 2/30 (7%) |
Ptosis | 0/11 | 2/30 (7%) |
Epicanthal folds | 5/11 (45%) | 9/30 (30%) |
Strabismus | 2/17 (12%) | 3/30 (10%) |
Wide nasal bridge | 6/11 (55%) | 4/30 (13%) |
Bulbous nose | 6/11 (55%) | 15/30 (50%) |
Full cheeks | 2/11 (18%) | 8/30 (27%) |
Malar hypoplasia | 5/11 (45%) | 3/30 (10%) |
Long philtrum | 3/11 (27%) | 5/30 (17%) |
Malocclusion | 7/11 (64%) | 5/30 (17%) |
Widely spaced teeth | 0/11 | 1/30 (3%) |
High arched palate | 6/10 (60%) | 8/30 (27%) |
Ear anomalies | 4/11 (36%) | 13/30 (43%) |
Pointed chin | 7/11 (64%) | 7/30 (23%) |
Large fleshy hands | 3/11 (27%) | 17/30 (57%) |
5th finger clinodactyly | 9/11 (82%) | 3/30 (10%) |
Syndactyly of toes 2–3 | 5/11 (45%) | 3/30 (10%) |
Hypoplastic/dysplastic nails | 7/11 (64%) | 11/30 (37%) |
Hyperextensibility | 6/10 (60%) | 8/30 (27%) |
Scoliosis | 1/11 (9%) | 7/30 (23%) |
Sacral dimple | 0/10 | 4/30 (13%) |
Gastroesophageal reflux | 5/17 (29%) | 13/30 (43%) |
Constipation/diarrhea | 11/17 (65%) | 11/30 (37%) |
Increased pain tolerance | 16/17 (94%) | 26/30 (87%) |
Recurrent infections | 9/17 (53%) | 16/30 (53%) |
Renal abnormalities | 0/17 | 12/30 (40%) |
Congenital heart defect | 1/17 (6%) | 1/30 (3%) |
Hypothyroidism | 0/17 | 1/30 (3%) |
Lymphedema | 0/17 | 7/30 (23%) |