Pacs1 Neurodevelopmental Disorder
Summary
Clinical characteristics.
PACS1 neurodevelopmental disorder (PACS1-NDD) is characterized by mild-to-severe neurodevelopmental delays. Language skills are more severely affected than motor skills. Hypotonia is reported in about a third of individuals and is noted to improve over time. Approximately 60% of individuals are ambulatory. Feeding difficulty is common, with 25% requiring gastrostomy tube to maintain appropriate caloric intake. Other common features include constipation, seizures, behavioral issues, congenital heart anomalies, short stature, and microcephaly. Common facial features include hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth. To date approximately 35 individuals with PACS1-NDD have been reported.
Diagnosis/testing.
The diagnosis of PACS1-NDD is established in a proband with a heterozygous pathogenic variant in PACS1 identified by molecular genetic testing.
Management.
Treatment: Standard treatment for feeding issues, constipation, seizures, behavioral issues, cardiac anomalies, vision issues, and renal anomalies.
Surveillance: Monitor for growth and nutrition issues, constipation, seizures, and behavioral issues. Monitor closure of septal defects as per cardiologist; monitor renal function if renal malformation is present as per nephrologist.
Agents/circumstances to avoid: Known seizure triggers.
Genetic counseling.
PACS1-NDD is an autosomal dominant disorder. All individuals reported to date have the disorder as the result of a de novo pathogenic variant. If the PACS1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
PACS1-NDD should be considered in individuals with the following clinical findings:
- Developmental delay and/or intellectual disability that are typically moderate, although range includes mild to severe delays
- Hypotonia
- Feeding difficulties
- Epilepsy (partial and tonic seizures reported, often with early or infantile onset; well-controlled by medication)
- Behavioral features (e.g., autism spectrum disorder, temper tantrums, aggression); overall friendly disposition in individuals of all ages
- Characteristic facial features (e.g., hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion, and wide-spaced teeth)
- Congenital heart anomalies (e.g., atrial septal defect, ventral septal defect, patent ductus arteriosus)
Establishing the Diagnosis
The diagnosis of PACS1-NDD is established in a proband with a heterozygous pathogenic variant in PACS1 by molecular genetic testing (see Table 1).
Note: Identification of a heterozygous PACS1 variant of uncertain significance does not establish or rule out a diagnosis of PACS1-NDD.
Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability typically begins with chromosomal microarray analysis (CMA). If CMA is not diagnostic, the next step is typically either a multigene panel or exome sequencing.
Note: (1) Single-gene testing (sequence analysis of PACS1) is rarely useful and typically NOT recommended. (2) Since PACS1-NDD likely occurs through a gain-of-abnormal-function or dominant-negative mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant.
An intellectual disability (ID) multigene panel that includes PACS1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition in a person with a nondiagnostic CMA at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of PACS1-NDD, some panels for ID may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an ID multigene panel with the additional advantage that exome sequencing includes genes recently identified as causing ID whereas some multigene panels may not. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by exome sequencing. Note: To date, such variants have not been identified as a cause of PACS1-NDD. Genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in PACS1 Neurodevelopmental Disorder
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| PACS1 | Sequence analysis 3 | ~35/35 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Since PACS1-NDD likely occurs through a gain-of-abnormal-function or dominant-negative mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
Clinical Characteristics
Clinical Description
To date, approximately 35 individuals with PACS1 neurodevelopmental disorder (PACS1-NDD) have been described in the literature [Schuurs-Hoeijmakers et al 2012, Chad et al 2015, Gadzicki et al 2015, Schuurs-Hoeijmakers et al 2016, Stern et al 2017, Martinez-Monseny et al 2018, Miyake et al 2018, Pefkianaki et al 2018, Dutta 2019, Hoshino et al 2019]. The following description of the phenotypic features associated with this condition is based on these reports.
Table 2.
Select Features of PACS1 Neurodevelopmental Disorder
| Feature | Proportion of Persons w/Feature | Comment |
|---|---|---|
| DD/ID | 35/35 |
|
| Feeding/ GI issues | 20-22/35 | Gastroesophageal reflux & constipation are most common manifestations. |
| Seizures | 20/35 |
|
| Characteristic behavioral features | 18/35 | Autism spectrum disorder present in ~25%-30% |
| Dysmorphic facial features | 35/35 | Hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set & simple ears, smooth philtrum, wide mouth w/downturned corners, thin upper vermilion (w/a "wavy" profile), wide-spaced teeth |
| Congenital heart anomalies | 15/35 | Atrial septal defects &/or ventricular septal defects in ~40% |
| Brain MRI findings | 13/20 | Hypoplasia or partial agenesis of the cerebellar vermis is most common finding |
| Ocular anomalies | 11/35 | Coloboma of the iris, retina, &/or optic nerve, myopia, strabismus, nystagmus |
DD = developmental delay; GI = gastrointestinal; ID = intellectual disability
Developmental delay and/or intellectual disability was reported in all individuals [Chad et al 2015, Schuurs-Hoeijmakers et al 2016, Stern et al 2017, Martinez-Monseny et al 2018, Miyake et al 2018, Pefkianaki et al 2018, Dutta 2019, Hoshino et al 2019]. Most had moderate delays, with a range of mild-to-severe delay and/or disability reported. Hypotonia was reported in about a third of individuals and was noted to improve over time. Approximately 60% of individuals are ambulatory, with onset of walking between age two and four years [Schuurs-Hoeijmakers et al 2016, Martinez-Monseny et al 2018, Pefkianaki et al 2018, Hoshino et al 2019]. Clumsiness and unsteady gait are reported. Regression in walking with frequent falls was noted in one individual. Two individuals use ambulatory assistive devices; one individual occasionally used a wheelchair from age ten years, and one individual required a walker from age 11 years, due to ataxia and a crouching gait [Schuurs-Hoeijmakers et al 2016]. Development of contractures has not been reported.
Language skills are universally affected, and more severely affected than motor skills. Most individuals develop verbal language, with several beginning to speak in their second year of life [Schuurs-Hoeijmakers et al 2016]. Two reported individuals started speaking in their third year of life [Schuurs-Hoeijmakers et al 2012, Gadzicki et al 2015]; one had meaningful words at age one year eight months and two-word sentences at age five years [Hoshino et al 2019], and one started using sentences at age eight years and was reading at age 11 years [Schuurs-Hoeijmakers et al 2016]. Seven out of 32 individuals were nonverbal at the time of evaluation, at ages two, three, four, six, ten, 11, and 20 years, respectively [Schuurs-Hoeijmakers et al 2016, Pefkianaki et al 2018, Hoshino et al 2019]. Stern et al [2017] reported that four of eight individuals were unable to speak more than a few words within the first three years of life. Three individuals were reported to have dysarthria [Stern et al 2017]. Of the individuals reported to be nonverbal, one was able to use sign language, picture exchange cards, and an iPad communication application [Schuurs-Hoeijmakers et al 2016], and one was unable to use sign language but able to use a communication board and demonstrated good receptive language skills [Pefkianaki et al 2018]. No individuals were reported to lose verbal skills.
Feeding difficulties / gastrointestinal issues. Poor weight gain and poor suck have been reported; oral aversion and a preference for soft foods were also reported. Difficulty with eating solid foods and poor weight gain may continue into adolescence and adulthood. Six of 27 individuals required a gastrostomy tube to maintain appropriate caloric intake [Schuurs-Hoeijmakers et al 2016, Stern et al 2017]. Constipation and reflux have been reported in several individuals. Delayed stomach emptying was reported in one individual.
Epilepsy. Seizures are present in about 50%-60% of reported individuals [Schuurs-Hoeijmakers et al 2016, Stern et al 2017, Martinez-Monseny et al 2018, Miyake et al 2018, Pefkianaki et al 2018, Dutta 2019, Hoshino et al 2019]. Seizure types have included partial and tonic seizures. Seizure onset has been reported as young as day two of life [Schuurs-Hoeijmakers et al 2012]. Seizures in individuals with PACS1-NDD have been well controlled by antiepileptic medications [Schuurs-Hoeijmakers et al 2016].
Behavior. Autism spectrum disorder occurs in about 25% to 30% of individuals. Temper tantrums and aggression are frequently reported, as is oral aversion and a preference for soft foods. Many individuals with PACS1-NDD, of all ages, are noted to have a happy, friendly disposition.
Facial features. All reported individuals have dysmorphic facial features [Chad et al 2015, Gadzicki et al 2015, Schuurs-Hoeijmakers et al 2016, Stern et al 2017, Martinez-Monseny et al 2018, Miyake et al 2018, Pefkianaki et al 2018, Dutta 2019, Hoshino et al 2019]. The most common features include: hypertelorism, downslanting palpebral fissures, bulbous nasal tip, low-set and simple ears, smooth philtrum, wide mouth with downturned corners, thin upper vermilion (with a "wavy" profile), and wide-spaced teeth.
Congenital heart anomalies were reported in about 45% of individuals [Schuurs-Hoeijmakers et al 2016, Stern et al 2017, Martinez-Monseny et al 2018, Hoshino et al 2019]. About 40% of individuals have an atrial septal defect and/or ventral septal defect. Additional cardiac defects include bicuspid aortic valve in two individuals [Schuurs-Hoeijmakers et al 2016, Martinez-Monseny et al 2018], dysplastic aortic and pulmonary valves [Schuurs-Hoeijmakers et al 2016], and dilation of pulmonary artery in one individual each [Stern et al 2017]. Additional cardiac findings have included patent ductus arteriosus and patent foramen ovale.
Growth. Abnormal height and weight measurements have been reported in 50%-60% of individuals. Approximately 40% of individuals have short stature and/or low weight [Schuurs-Hoeijmakers et al 2012, Chad et al 2015, Gadzicki et al 2015, Schuurs-Hoeijmakers et al 2016, Stern et al 2017, Pefkianaki et al 2018, Martinez-Monseny et al 2018, Miyake et al 2018, Hoshino et al 2019]; 5%-10% of these individuals are affected from birth, while 20% develop growth deficiency during childhood. Frequently, both weight and height are below average, although weight is more frequently affected than height. One individual with birth weight and length below the 10th centile had normal growth by age five years [Stern et al 2017]. Approximately 20% of individuals have microcephaly (7/33) [Schuurs-Hoeijmakers et al 2016, Miyake et al 2018, Dutta 2019]. Limited information is available regarding the onset of microcephaly, but Stern et al [2017] reported one individual with small head circumference (defined as <10th centile) at birth and also at age five years, one individual with small head circumference at birth and normal head circumference at age five years, and one individual with a normal head circumference at birth but a small head circumference at age 19 months.
Two individuals were greater than the 90th percentile for weight and/or length at birth, but had normal growth parameters at age three years and age 17 years [Stern et al 2017]. One individual with PACS1-NDD had sustained overgrowth and macrocephaly [Martinez-Monseny et al 2018].
Neuroimaging. Brain abnormalities have been identified in about 65% of individuals who have had imaging. The most frequent findings involve the cerebellar vermis (hypoplasia and partial agenesis). Additional findings include mild colpocephaly, ventriculomegaly/hydrocephalus ex vacuo, thin corpus callosum, frontal cortical dysplasia, paucity of cerebral white matter, mild delay in myelination, and hyperintensity of periventricular white matter.
Ocular anomalies. Coloboma of the iris, retina, and/or optic nerve was reported in 5/35 individuals, with three of five individuals reported to have bilateral coloboma [Schuurs-Hoeijmakers et al 2016, Pefkianaki et al 2018, Dutta 2019, Hoshino et al 2019]. Other ocular abnormalities reported include myopia, strabismus, and nystagmus.
Other
- Genitourinary abnormalities. Cryptorchidism has been reported in several males. Duplex kidney and hydronephrosis were reported in two individuals. Incontinence, renal agenesis, end-stage renal disease, urinary reflux, testicular microlithiasis, hypospadias and chordee, and bicornate uterus were each reported in one individual.
- Musculoskeletal features. Minor skeletal differences of the hands and feet are frequently reported, including clinodactyly or camptodactyly of the fifth fingers, tapered fingers, syndactyly, high plantar arch, pes planus, and broad great toe. Scoliosis occurred in three individuals [Author, personal communication]. Vertebral anomalies and pectus excavatum were each identified in one individual.
- Immunologic abnormalities have included frequent infections (3/33), leukopenia (1/33), neutropenia (1/33), and low immunoglobin levels (1/33) [Schuurs-Hoeijmakers et al 2016].
- Hearing loss. One individual had mild-to-moderate hearing loss of unknown type [Schuurs-Hoeijmakers et al 2016].
- Prognosis. It is unknown whether life span in individuals with PACS1-NDD is normal. One reported individual was alive at age 21 years [Schuurs-Hoeijmakers et al 2016], demonstrating that survival into adulthood is possible.
Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
Penetrance
To date, penetrance appears to be 100%.
Prevalence
Prevalence is currently unknown. Approximately 35 individuals with PACS1-NDD have been reported in the literature.
Differential Diagnosis
Because the phenotypic features associated with PACS1 neurodevelopmental disorder are not sufficient to diagnose this condition, all disorders with intellectual disability (ID) without other distinctive findings should be considered in the differential diagnosis. To date more than 180 such disorders with ID have been identified. See OMIM Phenotypic Series: Autosomal dominant ID; Autosomal recessive ID; Nonsyndromic X-linked ID; and Syndromic X-linked ID.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PACS1 neurodevelopmental disorder (PACS1-NDD), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with PACS1 Neurodevelopmental Disorder
| System/Concern | Evaluation | Comment |
|---|---|---|
| Development | Developmental assessment |
|
| Feeding issues / Gastrointestinal manifestations | Gastroenterology / nutrition / feeding team eval |
|
| Neurologic | Neurologic eval | Consider EEG if seizures are a concern. |
| Psychiatric / Behavioral | Neuropsychiatric eval | Individuals age >12 mos: screen for behavior concerns incl features of autism spectrum disorder |
| Cardiovascular | Echocardiogram | To evaluate for structural heart defects |
| Eyes | Ophthalmologic eval | To assess for ↓ vision, abnormal ocular movement, strabismus, or other anomalies |
| Genitourinary | Renal ultrasound | To evaluate for renal anomalies |
| Genetic counseling | By genetics professionals 1 | To inform patients & families re nature, MOI, & implications of PACS1-NDD to facilitate medical & personal decision making |
| Family support/ resources | Assess:
|
MOI = mode of inheritance
- 1.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with PACS1 Neurodevelopmental Disorder
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| DD/ID | See Developmental Delay / Intellectual Disability Management Issues. | |
| Poor weight gain |
| Feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia |
| Bowel dysfunction | Stool softeners, prokinetics, osmotic agents, or laxatives as needed for constipation | |
| Epilepsy | Standardized treatment w/AEDs by experienced child neurologist |
|
| Behavior | See Social/Behavioral Concerns. | |
| Cardiac anomalies | Treatment per cardiologist | |
| Abnormal vision &/or strabismus | Standard treatment(s) per ophthalmologist | |
| Renal anomalies | Treatment per nephrologist &/or urologist | |
| Family/ Community |
| Consider involvement in adaptive sports or Special Olympics. |
AED = antiepileptic drug; DD = developmental delay; ID = intellectual disability
- 1.
Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- Vision consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
- Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assessment should be carried out at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically by an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, an NG-tube or G-tube may be necessary.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairment to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech and in many cases, can improve it.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
Table 5.
Recommended Surveillance for Individuals with PACS1 Neurodevelopmental Disorder
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Development | Monitor developmental progress & educational needs. | At each visit |
| Feeding |
| |
| Gastrointestinal | Monitor for constipation. | |
| Respiratory | Monitor for evidence of aspiration, respiratory insufficiency. | |
| Neurologic |
| |