Clinical Description
To date, fewer than 50 individuals have been identified with a pathogenic variant in PPP2R1A [Houge et al 2015, Wallace et al 2019, Stenson et al 2020, Zhang et al 2020, Lenaerts et al 2021]. The following description of the phenotypic features associated with this condition is based on comprehensive clinical observations of individuals with confirmed pathogenic variants.
Table 2.
Select Features of PPP2R1A-Related Neurodevelopmental Disorder
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Feature | # of Persons w/Feature / # Assessed | Comment |
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Developmental delay | 37/37 (100%) | Ranging from mild to profound |
Language delay | 37/37 (100%) | Some persons remain nonverbal. |
Intellectual disability | 36/37 (97%) | Ranging from mild to profound, usually moderate to severe |
Delayed walking | 28/30 (93%) | Some persons remain nonambulatory. |
Hypotonia | 32/35 (91%) | Persistent into childhood & adulthood in 2 known persons |
Corpus callosum hypo-/aplasia | 22/33 (67%) | |
Head growth abnormalities | 22/36 (61%) | |
• Macrocephaly | 12/36 (33%) | See Genotype-Phenotype Correlations. |
• Microcephaly | 10/36 (28%) |
Feeding difficulties | 15/30 (50%) | Incl gastroesophageal reflux |
Epilepsy | 17/35 (49%) | See Genotype-Phenotype Correlations. |
Ventriculomegaly | 14/33 (42%) | Incl hydrocephalus |
Joint hypermobility | 14/37 (38%) | |
External ear abnormalities | 11/37 (30%) | Incl microtia |
Scoliosis | 9/37 (24%) | |
Delayed myelination | 6/33 (18%) | |
Hypoplasia of cerebellum / brain stem | 5/33 (15%) | |
Periventricular leukomalacia | 4/33 (12%) | |
Hearing loss | 4/37 (11%) | Incl sensorineural & hearing loss assoc w/microtia |
Short stature | 3/37 (8%) | |
Persistent ductus arteriosus | 3/37 (8%) | |
Developmental delay (DD) and intellectual disability (ID). The degree of DD is variable, but often in the moderate-to-severe range. DD in most affected individuals is global, affecting both cognitive and motor skills, but speech and language development and walking appear to be especially delayed.
The most severely affected individuals are typically nonambulatory, and those who learned to walk did so between ages one and five years (average age ~2 years).
Delayed/absent ambulation could be related to chronic hypotonia seen in most affected individuals.
One individual did not have ID but had a full-scale IQ of 86 and a clinical diagnosis of autism spectrum disorder [
Lenaerts et al 2021]; otherwise, all reported individuals have cognitive performance that falls within the range of ID (defined as a full-scale IQ score of <70).
Language delays are similarly variable, ranging from individuals with no speech and language development to those with relatively normal verbal language skills, but on average language development is moderately to severely delayed.
Hypotonia is a common feature, and unlike the transient neonatal hypotonia that is a feature of numerous syndromes, PPP2R1A-related hypotonia is long-lasting and possibly permanent.
Epilepsy is present in about half of affected individuals and is often associated with moderate-to-severe ID.
Individuals with microcephaly appear to be at an increased risk for developing epilepsy.
Most individuals with epilepsy develop seizures within the first year of life.
Seizure types and frequency are variable.
Behavior problems. Problems related to behavior and sleep were variably present but not in all individuals. The most common is attention-deficit/hyperactivity disorder, but anxiousness, repetitive movements, self-injurious or destructive behavior, and autism spectrum disorders have also been reported. Behavior problems are more commonly observed in those with epilepsy [Lenaerts et al 2021].
Feeding and growth
Feeding difficulties have been reported in about half of affected individuals and tend to be more common in those who are more severely affected.
Swallowing difficulties have been reported, causing gagging and/or choking with solid foods and necessitating soft or pureed foods.
Some affected individuals have gastroesophageal reflux disease that requires treatment (see
Management).
High palate (which can be associated with dental crowding) has been observed and contributes to feeding difficulties.
The severity is variable, but some individuals need gastrostomy tube placement.
Head circumference. Approximately two thirds of affected individuals present with abnormal head circumference, either macrocephaly (33%) or microcephaly (28%), which is usually congenital. While macrocephaly is usually nonprogressive, microcephaly can be progressive.
Most of the individuals with increased head size (macrocephaly) present with true megalencephaly, with a head circumference >3 SD and as high as 5.23 SD above the mean for age and sex in the absence of ventriculomegaly or hydrocephalus.
In individuals with microcephaly, head circumference is 3-6 SD below the mean for age and sex.
Length/height was within normal range in nearly 90% of affected individuals, and quite variable in individuals with the same pathogenic variant. Fewer than 10% have short stature (defined as length/height 2 SD below the mean for age and sex), and one had tall stature (defined as length/height 2 SD above the mean for age and sex) [
Lenaerts et al 2021].
Ears
Hearing loss has been reported in a minority (~10%) of individuals with
PPP2R1A-NDD [
Zhang et al 2020,
Lenaerts et al 2021]. In two individuals, the hearing loss was described as sensorineural; in another two individuals it was associated with microtia.
A range of external ear abnormalities not associated with hearing loss including low-set, small, cupped, simple, and asymmetric ears have also been reported.
Eyes. Although cortical blindness has been suspected in a few infants with severe features of PPP2R1A-NDD, no verified reports of eye or visual problems exist. However, ptosis can occur (probably as part of general muscular hypotonia).
Neuroimaging. Approximately two thirds of affected individuals have corpus callosum hypoplasia or aplasia, although almost one third have normal brain MRI findings.
Other associated features
Musculoskeletal features. In addition to hypotonia, generalized joint hypermobility and scoliosis have been reported in about one third of individuals. In two severely affected individuals, hip dislocations were also reported; one of the two also had a knee dislocation.
Cardiovascular. Persistent ductus arteriosus has been reported in three affected individuals (8%).
Facial features. Facial dysmorphism is frequently seen and can be partly associated with generalized hypotonia. Recurrent features include a long face with a tall forehead or frontal bossing (especially in those with macrocephaly), widely spaced eyes (hypertelorism), short palpebral fissures, a small nose with bulbous/prominent nasal tip, tented and/or thin vermilion of the upper lip, and, occasionally, ptosis [
Lenaerts et al 2021].
Prognosis. The life span of severely affected individuals with PPP2R1A-NDD can be shortened, especially in the presence of severe epilepsy that is refractory to treatment [Authors, personal communication]. In individuals with milder features, there are no life-limiting clinical comorbidities. Among the few reported individuals with PPP2R1A-NDD, several are in their third decade and not affected by life-limiting health problems [Lenaerts et al 2021]. Even though many PPP2R1A missense variants are also found somatically in tumors (see Cancer and Benign Tumors), no evidence so far would indicate that PPP2R1A-NDD is a cancer predisposition syndrome.
Genotype-Phenotype Correlations
Individuals with a heterozygous pathogenic variant that does not affect PPP2R1A binding to PPP2R2A (B55α) – for example, c.421T>A (p.Phe141Ile), c.532A>T (p.Thr178Ser), c.533C>A (p.Thr178Asn), c.539T>C (p.Met180Thr), and c.538A>G (p.Met180Val) – are more likely to have the following [Lenaerts et al 2021]:
Macrocephaly, defined as head circumference >2 SD for age and sex
Less severe intellectual disability
No seizures
Frontal bossing / long face
Individuals with pathogenic missense variants that are more likely to cause severe epilepsy – for example, c.536C>T (p.Pro179Leu), c.544C>T (p.Arg182Trp), and c.547C>T (p.Arg183Trp) – are also more likely to have more severe intellectual disability [Lenaerts et al 2021].
Microcephaly is most often associated with the following pathogenic missense variants: c.536C>T (p.Pro179Leu), c.773G>A (p.Arg258His), and c.772C>A (p.Arg258Ser).
Most individuals with the pathogenic variants c.544C>T (p.Arg182Trp) and c.547C>T (p.Arg183Trp) have ventriculomegaly.