Table 3.

Selected Disorders with Developmental Delay, Childhood Hypotonia, and Concurrent Findings Similar to Koolen-de Vries Syndrome

Gene / Genetic
Mechanism		DisorderMOIClinical CharacteristicsComment
22q11.2 deletion 22q11.2 deletion syndrome ADWide range of highly variable features; major clinical manifestations incl CHD (esp conotruncal malformations), palatal abnormalities, immune deficiency, characteristic facial features, & learning difficulties.KdVS may be considered in persons who tested negative for deletion of 22q11.2.
Deletions, maternal UPD, imprinting errors w/in PWCR 1Prader-Willi syndrome (PWS)See footnote 1.Severe hypotonia & feeding difficulties in early infancy, followed in later infancy / early childhood by excessive eating & gradual development of morbid obesity (unless eating is externally controlled); DD/ID; distinctive behavioral phenotype (w/temper tantrums, stubbornness, manipulative behavior, & obsessive-compulsive characteristics)Behavior issues & sleep disturbances are more common in PWS than in KdVS.
Disruption of maternally imprinted UBE3AAngelman syndrome (AS)See footnote 2.Severe DD/ID; severe speech impairment; gait ataxia &/or tremulousness of limbs; unique behavior w/apparent happy demeanor incl frequent laughing, smiling, & excitability; microcephaly & seizures are common.Research shows that prognosis for speech in persons w/KdVS is positive; apraxia resolves, & although dysarthria persists, most children are intelligible by mid-to-late childhood. 3 Speech delay in children w/AS remains far more severe. 4
BRAF
KRAS
MAP2K1
MAP2K2 		Cardiofaciocutaneous syndrome (CFC)ADVariable findings incl dysmorphic craniofacial features, cardiac issues, skin & hair abnormalities, hypotonia, eye abnormalities, GI dysfunction, seizures, & varying degrees of neurocognitive delay; polyhydramnios is present in vast majority of cases.Cutaneous features are more common in CFC. CFC & KdVS are further distinguished by differences in facial dysmorphisms.
FMR1 Fragile X syndrome (See FMR1 Disorders.)XLIn males, DD/ID w/behavioral issues; ASD in 50%-70% of affected persons; characteristic craniofacial features that become more obvious w/age; medical issues incl hypotonia & seizuresOveractivity, impulsivity, & challenging behavior are more common in fragile X syndrome than in KdVS.
KAT6B KAT6B disorders (incl genitopatellar syndrome & Say-Barber-Biesecker-Young-Simpson variant of Ohdo syndrome)ADBroad phenotypic spectrum w/variable expressivity; DD/ID; hypotonia; genital abnormalities; & skeletal abnormalitiesSevere ID, immobile mask-like facies, & abnormalities of thyroid structure or function are assoc w/KAT6B disorders. Skeletal issues are more common in KAT6B disorders than in KdVS.
KAT8 KAT8-related intellectual disability (Li-Ghorgani-Weisz-Hubshman syndrome)
(OMIM 618974)		ADDD/ID, epilepsy, & other developmental anomalies w/variable facial dysmorphismsStriking facial resemblance between KdVS & KAT8-related ID in some affected persons
WAC WAC-related intellectual disability ADVariable degrees of DD/ID; behavioral abnormalities incl anxiety, ADHD, &/or ASD are observed in majority of older children & adults. Most infants have significant but nonspecific features at birth such as neonatal hypotonia & feeding issues.Epilepsy is less common in WAC-related ID than in KdVS.

AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CHD = congenital heart defect; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PWCR = Prader-Willi critical region; UPD = uniparental disomy; XL = X-linked

1.

PWS is caused by an absence of expression of imprinted genes in the paternally derived PWS/Angelman syndrome (AS) region (i.e., 15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). The risk to the sibs of a proband with PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.

2.

The risk to sibs of a proband with Angelman syndrome depends on the genetic mechanism leading to the loss of UBE3A function.

3.
4.

From: Koolen-de Vries Syndrome

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