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.

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 (or likely pathogenic) variant in PACS1 by molecular genetic testing (see Table 1). Identification of a heterozygous PACS1 variant of uncertain significance does not establish or rule out a diagnosis of PACS1-NDD.

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

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-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 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.

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.

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, as a result of 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 anti-seizure medication [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 dilatation 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.

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.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Individuals with PACS1-NDD should avoid any known seizure triggers (e.g., sleep deprivation, alcohol use, missed medications).

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

PACS1 neurodevelopmental disorder (PACS1-NDD) is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• All of the 31 probands with PACS1-NDD reported in the literature whose parents have undergone molecular genetic testing have had the disorder as a result of a de novo PACS1 pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the PACS1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is that the proband inherited a pathogenic variant from a parent with germline mosaicism. Although theoretically possible, no instances of parental mosaicism have been reported to date.
• Theoretically, if the parent is the individual in whom the PACS1 pathogenic variant first occurred, the parent may have somatic and germline mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to sibs of the proband depends on the genetic status of the proband's parents: 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 [Rahbari et al 2016].

Offspring of a proband. Individuals with a PACS1-NDD are not known to reproduce due to their neurodevelopmental disability; however, many are not yet of reproductive age.

Other family members. Given that all probands with PACS1-NDD reported to date have the disorder as a result of a de novo PACS1 pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo PACS1 pathogenic variant. There is, however, a recurrence risk (~1%) to sibs based on the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Given this risk, prenatal testing and preimplantation genetic testing may be considered.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

PACS1 encodes PACS1, a trans-golgi-membrane traffic regulator [Schuurs-Hoeijmakers et al 2012] involved in directing protein cargo and cranial-neural-crest cell migration. Expression is upregulated during embryonic brain development, with low expression after birth.

An R¹⁹⁶RKRY CK2-binding motif is critical to PACS1 autoregulation [Schuurs-Hoeijmakers et al 2012]. Disease-associated variants occur at p.Arg203 in the furin(cargo)-binding domain, directly adjacent to the CK2-binding motif and may affect interaction with cargo. The introduction of the p.Arg203Trp pathogenic variant led to protein-trafficking defects, cellular aggregates, and abolishment of normal PACS1 function [Schuurs-Hoeijmakers et al 2012, Schuurs-Hoeijmakers et al 2016]. The craniofacial phenotype of PACS1 neurodevelopmental disorder is suggested to be a result of impairment in the specification and migration of cranial-neural-crest cells.

Mechanism of disease causation. Recurrent disease-associated variants in the same codon, c.608G>A and c.607C>T, as well as studies in zebrafish, suggest either a dominant-negative or gain-of-function disease mechanism [Schuurs-Hoeijmakers et al 2012, Miyake et al 2018].

Identification of several individuals with the same de novo variant suggests positive selection for the c.607C>T variant during spermatogenesis, similar to positive selection for FGFR3 pathogenic variants [Schuurs-Hoeijmakers et al 2016]. The c.608G>A variant did occur on the paternal chromosome [Miyake et al 2018]. Data are insufficient at this time to comment on paternal age effects.

Revision History

• 16 July 2020 (sw) Review posted live
• 30 March 2020 (wc) Original submission

Literature Cited

• Chad L, Chung B HY, Marshall CR, Merico D, Babul-Hirji R, Stavropoulos DJ, Chitayat D. Global developmental delay and characteristic facial features associated with PACS1 gene mutation – report of two cases. J Med Genet. 2015;52 Suppl 1:A1.
• Dutta AK. Schuurs-Hoeijmakers syndrome in a patient from India. Am J Med Genet Part A. 2019;179:522–4. [PubMed: 30690871]
• Gadzicki D, Döcker D, Schubach M, Menzel M, Schmorl B, Stellmer F, Biskup S, Bartholdi D. Expanding the phenotype of a recurrent de novo variant in PACS1 causing intellectual disability. Clin Genet. 2015;88:300–2. [PubMed: 25522177]
• Hoshino Y, Enokizono T, Imagawa K, Tanaka R, Suzuki H, Fukushima H, Arai J, Sumazaki R, Uehara T, Takenouchi T, Kosaki K. Schuurs-Hoeijmakers syndrome in two patients from Japan. Am J Med Genet Part A. 2019;179:341–3. [PubMed: 30588754]
• Kaplanis J, Akawi N, Gallone G, McRae JF, Prigmore E, Wright CF, Fitzpatrick DR, Firth HV, Barrett JC, Hurles ME. Deciphering Developmental Disorders study. Exome-wide assessment of the functional impact and pathogenicity of multinucleotide mutations. Genome Res. 2019;29:1047–56. [PMC free article: PMC6633265] [PubMed: 31227601]
• Martinez-Monseny A, Bolasell M, Arjona C, Martorell L, Yubero D, Arsmtrong J, Maynou J, Fernandez G, del Carmen Salgado M, Palau F, Serrano M. Mutation of PACS1: the milder end of the spectrum. Clin Dysmorphol. 2018;27:148–50. [PubMed: 30113927]
• Miyake N, Ozasa S, Mabe H, Kimura S, Shiina M, Imagawa E, Miyatake S, Nakashima M, Mizuguchi T, Takata A, Ogata K, Matsumoto N. A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome. Clinical Genet. 2018;93:929–30. [PubMed: 28975623]
• Pefkianaki M, Schneider A, Capasso JE, Wasserman B, Bardakjian T, Levin AV. Ocular manifestations of PACS1 mutation. J AAPOS. 2018;22:323–5. [PubMed: 29550517]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Schuurs-Hoeijmakers J HM, Landsverk ML, Foulds N, Kukolich MK, Gavrilova RH, Greville-Heygate S, Hanson-Kahn A, Bernstein JA, Glass J, Chitayat D, Burrow TA, Husami A, Collins K, Wusik K, van der Aa N, Kooy F, Tatton Brown K, Gadzicki D, Kini U, Alvarez S, Fernández-Jaén A, McGehee F, Selby K, Tarailo-Graovac M, Van Allen M, van Karnebeek C DM, Stavropoulos DJ, Marshall CR, Merico D, Gregor A, Zweier C, Hopkin RJ, Wing-Yiu Chu Y, Chung B HY, de Vries B BA, Devriendt K, Hurles ME, Brunner HG. DDD study. Clinical delineation of the PACS1-related syndrome—report on 19 patients. Am J Med Genet. 2016;170:670–5. [PubMed: 26842493]
• Schuurs-Hoeijmakers J HM, Oh EC, Vissers L. ELM, Swinkels M EM, Gilissen C, Willemsen MA, Holvoet M, Steehouwer M, Veltman JA, de Vries B BA, van Bokhoven H, de Brouwer A PM, Katsanis N, Devriendt K, Brunner HG. Recurrent de novo mutations in PACS1 cause defective cranial-neural-crest migration and define a recognizable intellectual-disability syndrome. Am J Hum Genet. 2012;91:1122–7. [PMC free article: PMC3516611] [PubMed: 23159249]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Stern D, Cho MT, Chikarmane R, Willaert R, Retterer K, Kendall F, Deardorff M, Hopkins S, Bedoukian E, Slavotinek A, Schrier Vergano S, Spangler B, McDonald M, McConkie-Rosell A, Burton BK, Kim KH, Oundjian N, Kronn D, Chandy N, Baskin B, Guillen Sacoto MJ, Wentzensen IM, McLaughlin HM, McKnight D, Chung WK. Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures. Clin Genet. 2017;92:221–3. [PMC free article: PMC5513756] [PubMed: 28111752]