Clinical characteristics.

White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), hypotonia, autism spectrum disorder, and other behavioral problems. Additional features commonly reported include seizures, refractive errors and strabismus, hearing loss, sleep disturbance (particularly sleep apnea), feeding and gastrointestinal problems, mild genital abnormalities in males, and urinary tract involvement in both males and females.

Diagnosis/testing.

The diagnosis of White-Sutton syndrome is established in a proband with suggestive findings and a heterozygous pathogenic variant in POGZ identified by molecular genetic testing.

Management.

Treatment of manifestations: Developmental delay/intellectual disability, speech and language acquisition, behavioral issues, seizures, refractive errors and strabismus, hearing impairment, sleep disturbance, feeding and gastrointestinal issues, and genitourinary problems are managed by specialists per standard care.

Surveillance: Follow up of the common manifestations at each clinic visit.

Genetic counseling.

White-Sutton syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Most probands reported to date whose parents have undergone molecular genetic testing have the disorder as the result of a de novo POGZ pathogenic variant. Rarely, individuals with White-Sutton syndrome have the disorder as the result of a POGZ pathogenic variant inherited from a heterozygous parent with features such as developmental delay and/or mild intellectual disability. Once the POGZ pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

White-Sutton syndrome should be considered in individuals with the following clinical and brain MRI findings.

Clinical findings

• Mild-to-severe developmental delay, intellectual disability, or learning difficulties
• Speech delay

AND

• Any of the following features presenting in infancy or childhood:
  Common features
  • Motor delay
  • Generalized hypotonia
  • Behavioral problems such as anxiety, attention-deficit/hyperactivity disorder, aggression towards self or others, and sleep disturbance
  • Autism / autism spectrum disorder
  • Microcephaly
  • Infant feeding difficulties that may require tube feeding or gastrostomy
  • Gastrointestinal manifestations including constipation, gastroesophageal reflux, and cyclic vomiting
  • Tendency toward being overweight
  Less common features
  • Epilepsy with both focal and generalized seizures that generally respond to anti-seizure medications
  • Ophthalmologic abnormalities such as strabismus, optic nerve hypoplasia, and refractive errors including myopia, hypermetropia, and astigmatism
  • Sensorineural hearing impairment / cochlear dysfunction
  • Sleep-disordered breathing
  • Congenital diaphragmatic hernia
  • Mild male genital anomalies such as cryptorchidism or micropenis
  • Congenital anomalies of the kidney and urinary tract such as duplicated collecting system
  • Recurrent infections
  • Palate abnormalities such as high-arched palate, cleft palate, or bifid uvula

While some facial features are frequently observed, the authors believe that this syndrome cannot be definitively diagnosed clinically based on facial or other phenotypic features alone (see Clinical Description and Assia Batzir et al [2020], Figure 2).

Establishing the Diagnosis

The diagnosis of White-Sutton syndrome is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in POGZ identified by molecular genetic testing (see Table 1).

Note: (1) 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. (2) Identification of a heterozygous POGZ variant of uncertain significance itself does not establish or rule out the diagnosis.

Molecular genetic testing in a child with developmental delay or an older individual with intellectual disability may begin with chromosomal microarray analysis (CMA). Other options include use of a multigene panel or exome sequencing. Note: Single-gene testing (sequence analysis of POGZ, followed by gene-targeted deletion/duplication analysis) would generally NOT be recommended, as the phenotypic features of White-Sutton syndrome are relatively nonspecific.

• An intellectual disability multigene panel that includes POGZ 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 White-Sutton syndrome, some panels for intellectual disability 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. 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

White-Sutton syndrome is a neurodevelopmental disorder characterized by a wide spectrum of cognitive dysfunction, developmental delays (particularly in speech and language acquisition), and autism spectrum disorder (ASD) as well as other behavioral problems. Additional features commonly reported include hypotonia, gastrointestinal problems, seizures, microcephaly, sensorineural hearing loss, strabismus, short stature, tendency towards obesity, and sleep disturbance (particularly sleep apnea).

To date, more than 90 individuals have been identified with a pathogenic variant in POGZ [Gulsuner et al 2013, Gilissen et al 2014, Iossifov et al 2014, Deciphering Developmental Disorders Study Group 2015, Fukai et al 2015, Homsy et al 2015, Ye et al 2015, Hashimoto et al 2016, Stessman et al 2016, Tan et al 2016, White et al 2016, Dentici et al 2017, Du et al 2018, Ferretti et al 2019, Zhao et al 2019, Assia Batzir et al 2020, Pascolini et al 2020, Samanta et al 2020, Dal et al 2021, Donnarumma et al 2021, Garde et al 2021, Liu et al 2021, Trimarchi et al 2021, Türay & Eröz 2021, Wright et al 2022]. Table 2 and the following description of the phenotypic features associated with this condition are based on these reports.

Intellectual disability / learning difficulties. Virtually all individuals reported to date have learning difficulties or intellectual disability ranging from mild (36%-50%) to profound (≤32%). Assessment of various cognitive domains in five individuals identified deficiencies in language and attention, as well as executive and social dysfunction that affected their daily lives (especially in communication) [Garde et al 2021]. Although information on cognitive function in adults is limited, some adults are able to work, care for themselves, and raise children [Assia Batzir et al 2020; Garde et al 2021; Liu et al 2021; Wright et al 2022; Authors, personal experience].

Speech delay is seen in nearly all affected individuals, and is generally more pronounced than motor delays. While first words often emerge at an appropriate age, the formation of sentences may be delayed until the school-age years; some remain nonverbal after age six years [Assia Batzir et al 2020, Garde et al 2021]. Despite language difficulties, verbal comprehension appears to be less affected.

Although information on cognitive function in adults is limited, adults may be able to work and care for themselves, and in some instances raise children [Assia Batzir et al 2020; Garde et al 2021; Liu et al 2021; Wright et al 2022; Authors, personal experience].

Motor delay is common. Reported age at onset of walking ranges from before 12 months to six years [Assia Batzir et al 2020, Garde et al 2021]. Delays may be related to hypotonia that presents as early as the first days of life. Hypotonia is seen in the vast majority of individuals and may be the first sign that brings the child to medical attention.

Additional causes for motor delays include medical issues such as complex abdominal surgery and lower limb spasticity. Gait abnormalities including clumsiness and difficulty with coordination have also been reported.

Although a movement disorder is not frequently seen, paroxysmal nonepileptic events have been described in at least two individuals [Ferretti et al 2019, Donnarumma et al 2021].

Behavior problems include issues with attention, anxiety, irritability, and aggression toward oneself or others. In their assessment of neuropsychological profiles of 19 individuals with White-Sutton syndrome, Garde et al [2021] observed common behavioral characteristics including immature behavior (7 individuals), significant slowness (7), and attention disorder (8) that were associated with either excessive inhibition and withdrawal or lack of inhibition leading to agitation, opposition, or provocation.

ASD was observed in up to 50% of individuals reported in the literature. Repetitive behaviors [Wang et al 2016], restricted interests, and stereotypic movements of the hands or mouth have been described [Stessman et al 2016, Dentici et al 2017, Donnarumma et al 2021].

Epilepsy. Both generalized and tonic and focal epilepsy, as well as febrile seizures and EEG abnormalities without overt convulsions, occur in approximately 20% of affected individuals [Pascolini et al 2020, Samanta et al 2020]. Epileptic seizures precipitated by bathing/showering in hot water were reported in one individual [Türay & Eröz 2021].

While onset of seizures ranges from infancy to adolescence, it is typically between ages one and four years. Seizures are generally controlled either by monotherapy or with multiple anti-seizure medications, and may resolve with age. Status epilepticus has not been reported.

Information on EEG patterns is limited. Findings may include epileptic abnormalities localized to the frontal region or bitemporal sharp waves and are not specific to this disorder [Stessman et al 2016, White et al 2016, Ferretti et al 2019, Samanta et al 2020].

Neuroimaging. Brain imaging reveals central nervous system abnormalities in up to two thirds of affected individuals. When present, brain MRI abnormalities are variable and nonspecific. Recurring features include small foci in the deep white matter on T₂/FLAIR imaging, prominence of cerebrospinal fluid in the posterior fossa, and cerebellar dysgenesis [Samanta et al 2020]. Thin corpus callosum, abnormal myelination, polymicrogyria, small optic chiasm / optic nerve hypoplasia, persistent cavum septum pellucidum, and Dandy-Walker spectrum malformations have also been described [Ye et al 2015, Dentici et al 2017, Assia Batzir et al 2020, Samanta et al 2020].

Ophthalmologic abnormalities that can impair vision include retinal dystrophy (3 individuals) [White et al 2016, Assia Batzir et al 2020], optic nerve hypoplasia (3) [White et al 2016, Assia Batzir et al 2020], Horner syndrome (2) [Gilissen et al 2014, White et al 2016], and coloboma (1) [White et al 2016]. Treatable conditions can include refractive errors (astigmatism, myopia, or hyperopia) and strabismus.

Hearing loss, reported in approximately one third of individuals, can be conductive secondary to recurrent middle ear infections or sensorineural with cochlear dysfunction.

Sleep disorders. Families of individuals with White-Sutton syndrome often report problems with sleep (e.g., difficulty falling asleep, frequent awakenings, sleepwalking).

Sleep apnea is known to occur; a sleep disorder survey completed for 12 individuals revealed features suggestive of obstructive sleep apnea in four [Assia Batzir et al 2020].

Feeding/gastrointestinal problems. Feeding difficulties, which are common, may be severe enough to require nasogastric tube feeding or gastrostomy. These problems can be related to gastroesophageal reflux, feeding intolerance with gastric distention, problems with chewing or swallowing, or oversensitivity of the oral region resulting in food aversion.

Vomiting is common. Some individuals experience recurring episodes of vomiting in childhood with or without a cyclical pattern. Vomiting tends to improve or resolve with age; some parents report that nausea and vomiting appear to respond to therapies for "abdominal migraines" [Assia Batzir et al 2020; Authors, personal communication].

Gastrointestinal manifestations requiring surgery can include intestinal malrotation, ventral and inguinal hernia, and rectal prolapse.

Congenital diaphragmatic hernia, although infrequently described, is a recurring finding [White et al 2016, Longoni et al 2017, Assia Batzir et al 2020, Garde et al 2021].

Genitourinary abnormalities. Congenital anomalies of the kidneys and urinary tract can include dysplastic kidneys as well as duplicated collecting system, hydronephrosis, and/or megaureter. Male genital anomalies can include undescended testes, hypoplastic scrotum/testes, and micropenis.

Recurrent infections. Frequent respiratory, ear, and bladder infections were reported in several individuals; one individual was diagnosed with immune deficiency. One individual had low titers to vaccines [Authors, personal experience].

Musculoskeletal. Minor abnormalities of the fingers and toes (e.g., brachydactyly, broad thumbs or first toes, and spatulate fingers) and joint laxity may be seen. Clubfeet, joint contractures, and syndactyly are rare.

Growth. Although growth parameters at birth are usually within the normal range, intrauterine growth restriction has been documented in approximately 20% of individuals for whom data were available.

Height and weight range from below the third percentile to above average. Short stature or failure to gain weight have been reported in approximately 15% of individuals [Fukai et al 2015, Stessman et al 2016, Tan et al 2016, Dentici et al 2017, Ferretti et al 2019, Zhao et al 2019, Assia Batzir et al 2020, Pascolini et al 2020, Garde et al 2021].

Despite initial problems with feeding, a significant proportion of children become overweight, as early as the first years of life [Stessman et al 2016].

Microcephaly (head circumference <3rd percentile) is common.

Other. Although minor cardiovascular abnormalities including atrial septal defect / patent foramen ovale, bicuspid aortic valve, and mild dilatation of the ascending aorta have been reported, it is unclear if these occur at a higher frequency in White-Sutton syndrome than in the general population.

Craniofacial features may include microcephaly, brachycephaly, high and broad forehead, hypertelorism, broad and/or high nasal root, anteverted nares, long malar region with midface hypoplasia/retrusion, prognathism, downturned corners of the mouth, palate abnormalities (high-arched palate, cleft palate, bifid uvula), and low-set ears. While these facial features are frequently observed, the authors believe that a definitive clinical diagnosis of this syndrome cannot be made based solely on facial or other phenotypic features.

Prognosis. It is unknown whether life span in individuals with White-Sutton syndrome is decreased. The oldest known individual was age 36 years at time of report [Wright et al 2022]. One affected individual (age not reported) has an affected son, age 15 years [Liu et al 2021]. Instances of parent-to-child transmission [Assia Batzir et al 2020, Garde et al 2021, Liu et al 2021] demonstrate that survival into adulthood and raising a family are possible.

Genotype-Phenotype Correlations

While no clear genotype-phenotype correlations have been identified, the following are general observations:

• Missense variants are not clearly associated with cognitive problems but appear to be associated with behavioral issues including ASD or autistic-like behaviors [Stessman et al 2016].
• In 20 individuals with White-Sutton syndrome with nonsense, frameshift, or copy number variants in POGZ, variants in exons 18-19, which were predicted to escape nonsense-mediated RNA decay (NMD), were more likely to be associated with lack of speech and more severe gastrointestinal complications that required surgery (such as malrotation, rectal prolapse, and congenital diaphragmatic hernia). Variants that occurred in exons 6, 8, 9, 10, and 15, and one deletion of exons 4-19, predicted to undergo NMD, were more frequently associated with milder neurocognitive deficiencies [Assia Batzir et al 2020].
• Behavioral problems, sleep disorders, gastrointestinal manifestations, and microcephaly were more frequently associated with variants in the DDE domain of the protein (encoded by part of exon 19), whereas central nervous system and genitourinary malformations occurred more often with variants affecting other protein domains [Pascolini et al 2020].

Prevalence

To date, more than 90 individuals with White-Sutton syndrome have been reported.

Exome sequencing of 9,206 individuals with neurodevelopmental disorders identified pathogenic or likely pathogenic variants in POGZ in 13 (i.e., 1.4:1,000 or 0.14%) [Assia Batzir et al 2020].

Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.

Penetrance

To date, when parental data were available, all reported instances of loss-of-function variants in POGZ associated with White-Sutton syndrome were either de novo or inherited from an affected parent. Published information indicates that all nonsense POGZ variants are fully penetrant.

The penetrance of missense POGZ variants may be reduced; however, data are limited.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with White-Sutton syndrome, 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

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Following studies in mice that suggested a role for the oxytocin system in autism spectrum disorders, Kitagawa et al [2021] observed that intranasal oxytocin administration was able to restore the impaired social behavior in a mouse model heterozygous for the Pogz missense variant Gln1038Arg. No studies on the effect of oxytocin treatment in humans have been published to date.

Behavioral abnormalities in a mouse model of White-Sutton syndrome improved when treated with the anti-seizure medication perampanel [Matsumura et al 2020]. Perampanel has NOT been studied in individuals with White-Sutton syndrome.

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.

Mode of Inheritance

White-Sutton syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with White-Sutton syndrome whose parents have undergone molecular genetic testing have the disorder as the result of a de novo POGZ pathogenic variant.
• Rarely, individuals diagnosed with White-Sutton syndrome have the disorder as the result of a POGZ pathogenic variant inherited from a heterozygous parent with mild features of the syndrome such as developmental delay and/or mild intellectual disability.
• Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents:

• If a parent of the proband is known to have the POGZ pathogenic variant identified in the proband, the risk to the sibs of inheriting the variant is 50%.
• If the POGZ 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. Each child of an individual with White-Sutton syndrome has a 50% chance of inheriting the POGZ pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the POGZ pathogenic variant, the parent's family members may be at risk.

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 young adults who are affected and to the parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the POGZ pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

POGZ (pogo-transposable element with ZNF domain) encodes a heterochromatin protein involved in chromatin condensation with robust expression in developing neuronal progenitor cells. Functionally, POGZ has been shown to be important for neuronal differentiation and development [Matsumura et al 2020]. Dysregulation of chromatin architecture in developing neurons and the resulting alteration of neuronal transcription likely underlie the cellular pathogenesis. Indeed, disruption of chromatin architecture is an etiology shared among various neurodevelopmental disorders, in which POGZ has become one of the most commonly mutated genes observed in large cohorts of neurodevelopmental disorders [Satterstrom et al 2020].

The majority of pathogenic variants reported thus far create premature termination codons, although many are located in the final exon and are thus not expected to undergo nonsense-mediated decay. In addition, some single-nucleotide missense variants have demonstrated functional defects, such as impaired DNA binding [Matsumura et al 2020].

Mechanism of disease causation. Given the preponderance of heterozygous truncating variants and functional characterization of missense alteration, loss of function resulting in haploinsufficiency is the most likely mechanism of pathogenicity.

Author Notes

V Reid Sutton's website: www.bcm.edu

Acknowledgments

We would like to acknowledge James Lupski, Christine Beck, Tamar Harel, and Jennifer Posey, who were instrumental in the initial description of White-Sutton syndrome. The work that led to the initial description was supported by the US National Human Genome Research Institute (NHGRI) / National Heart Lung and Blood Institute (NHLBI) Grant No. HG006542 to the Baylor-Hopkins Center for Mendelian Genomics. We would also like to thank the White-Sutton Syndrome Foundation and families for their continued support in our research endeavors.

Revision History

• 16 September 2021 (bp) Review posted live
• 2 July 2021 (vrs) Original submission

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