Clinical characteristics.

Koolen-de Vries syndrome (KdVS) is characterized by congenital malformations, developmental delay / intellectual disability, neonatal/childhood hypotonia, epilepsy, dysmorphisms, and behavioral features. Psychomotor developmental delay is noted in all individuals from an early age. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability. Other findings include speech and language delay (100%), epilepsy (~33%), congenital heart defects (25%-50%), renal and urologic anomalies (25%-50%), and cryptorchidism. Behavior in most is described as friendly, amiable, and cooperative.

Diagnosis/testing.

The diagnosis of KdVS is established in a proband who has either a heterozygous 500- to 650-kb deletion at chromosome 17q21.31 that includes KANSL1 or a heterozygous intragenic pathogenic variant in KANSL1. Note: The 17q21.31 deletion cannot be identified by analysis of G-banded chromosomes or other cytogenetic banding techniques.

Management.

Treatment of manifestations: Supportive care, ideally through a multidisciplinary team of specialists, to improve quality of life, maximize function, and reduce complications is recommended. Speech therapy to support early feeding challenges and communication development; physiotherapy for gross and fine motor delays; educational programs directed to specific disabilities identified. Growth hormone therapy is indicated for those with growth hormone deficiency. Routine treatment of vision issues / strabismus; hearing loss; cardiac, renal, and urologic issues; epilepsy; scoliosis, hip dislocation, and positional deformities of the feet; multiple nevi.

Surveillance: At each visit: measurement of growth parameters; evaluation of nutritional status and safety of oral intake; monitoring of developmental progress and educational needs; assessment for new manifestations, such as seizures and changes in tone; behavioral assessment; assessment of mobility and self-help skills. Annual full skin examination in those with lighter skin tones or skin types who are at greater risk for developing melanoma. Ophthalmology and hearing evaluations annually or as clinically indicated.

Genetic counseling.

KdVS, caused by a heterozygous deletion at chromosome 17q21.31 or a heterozygous intragenic KANSL1 pathogenic variant, is an autosomal dominant disorder. Almost all affected individuals represent simplex cases (i.e., a single affected individual in the family).The recurrence risk for future pregnancies is slightly greater than that of the general population because of the possibility of germline mosaicism in one of the parents. Once the KdVS-related genetic alteration has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

KdVS should be considered in probands with the following clinical and family history findings.

Clinical findings

• Mild-to-moderate developmental delay or intellectual disability in which speech and language development is particularly affected

AND

• Neonatal/childhood hypotonia and feeding difficulties
• Epilepsy
• Dysmorphic facial features (See Clinical Description and Figure 1.)
• Hypermetropia
• Congenital heart anomalies
• Congenital renal/urologic anomalies
• Hypermobility of the joints and/or joint dislocation/dysplasia
• Deformities of the spine and/or feet

Figure 1.

Photographs of eight individuals with a 17q21.31 deletion

Family history. Because KdVS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

The diagnosis of KdVS is established in a proband with typical clinical findings and of any of the following (see Table 1):

• A heterozygous deletion at chromosome 17q21.31 that includes KANSL1 (~60% of affected individuals). The 17q21.31 deletion is typically 500 to 650 kb in size (hg19: chr17:43,700,000-44,250,000) and is flanked by segmental duplications.
• A heterozygous intragenic pathogenic (or likely pathogenic) variant in KANSL1 (~40% of affected individuals)
• Haploinsufficiency of KANSL1 due to chromosome rearrangements [Moreno-Igoa et al 2015]

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" 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 KANSL1 variant of uncertain significance does not establish or rule out the diagnosis. (3) A characteristic epigenetic signature for KdVS has been established and may aid in the determination of the clinical significance of uncertain variants (see Further Testing to Consider).

Molecular genetic testing approaches can include a combination of gene-targeted testing (chromosomal microarray analysis, single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of KdVS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Koolen-de Vries syndrome (KdVS) has a clinically recognizable phenotype that includes neonatal/childhood hypotonia, developmental delay / intellectual givdisability, dysmorphisms (see Figure 1), speech and language delays, congenital malformations, and behavioral features. To date, more than 200 individuals have been identified with KdVS [Koolen et al 2006, Sharp et al 2006, Koolen et al 2008, Grisart et al 2009, Tan et al 2009, Koolen et al 2012b, Zollino et al 2012, Zollino et al 2015, Koolen et al 2016, Morgan et al 2018a, Myers et al 2017, Amenta et al 2022, St John et al 2022]. The following description of the phenotypic features associated with this condition is based on these reports.

Dysmorphic craniofacial features that may suggest KdVS include:

• Upslanted palpebral fissures
• Blepharophimosis
• Epicanthus
• Ptosis
• Pear-shaped nose
• Bulbous nose
• Large/protruding ears

The nose can have a high nasal bridge, a broad nasal root, long columella, and underdeveloped and/or thick alae nasi. The facial characteristics change with age. In infancy the facial gestalt is mostly characterized by hypotonia with an "open mouth" appearance. With increasing age there is usually elongation of the face and broadening of the chin, and the "tubular'' or "pear'' shape of the nose may become more apparent.

Developmental delay / intellectual disability. Psychomotor delay is noted in all affected individuals from an early age. The level of developmental delay varies significantly. The majority of individuals with KdVS function in the mild-to-moderate range of intellectual disability.

• Communication disorder is a core feature of KdVS, with a common speech and language phenotype seen. This includes an overriding "double hit" of oral hypotonia and apraxia in infancy and preschool, associated with severely delayed speech development [Morgan et al 2018a]. St John et al [2022] defined speech, language, and functional/adaptive behavior in 81 individuals with KdVS.
  • First words occur on average between ages 2.5 and 3.5 years.
  • Childhood apraxia of speech (CAS) is common in the preschool years, and speech development is effortful even when supported with intensive therapy.
    Augmentative (e.g., sign language) or alternative (e.g., communication devices) communication may alleviate frustration for the child and promote communication development.
    Overall, however, speech prognosis is positive, with CAS improving markedly around age eight to 12 years. At this time, the dysarthric element of speech is more apparent with a slow rate and monotone presentation.
  • Stuttering has been described in 76.6% of verbal individuals and follows a unique trajectory of late onset and fluctuating presence [St John et al 2022].
  • Receptive and expressive language abilities are commensurate, but literacy skills remain a relative weakness.
  • Social competence, successful behavioral/emotional control, and coping skills are areas of relative strength, while communication difficulties affect daily living skills as an area of comparative difficulty.

Hypotonia with poor sucking and slow feeding can be evident in the neonatal period and during childhood. Feeding difficulties may require hospitalization and/or nasogastric tube feeding in some neonates. Beyond infancy and into the preschool years, many children experience issues chewing difficult, lumpy, or solid textures [Morgan et al 2018a].

Epilepsy, including generalized seizures and unilateral clonic seizures, is noted in approximately 33% of affected individuals. The epilepsy phenotypic spectrum in KdVS is broad; however, most individuals have focal seizures, with some having a phenotype resembling the self-limited focal epilepsies of childhood [Myers et al 2017].

• The typical epilepsy phenotype of KdVS involves childhood-onset focal seizures that are prolonged and have prominent autonomic features.
• Multifocal epileptiform discharges are the typical EEG pattern.

Neurobehavioral/psychiatric manifestations. In many affected individuals, behavior is described as friendly, amiable, and cooperative, with or without frequent laughing. However, behavioral findings including attention-deficit/hyperactivity disorder have been reported [Koolen et al 2008, Tan et al 2009, Koolen et al 2016]. A subset of affected individuals have autism and/or anxiety.

Growth. Short stature is not one of the most common clinical features of the syndrome. However, El Chehadeh-Djebbar et al [2011] reported a child with a 17q21.31 deletion, short stature (4 SD below the mean), complete growth hormone deficiency, and gonadotropic deficiency [El Chehadeh-Djebbar et al 2011]. Brain MRI showed partial pituitary stalk interruption, expanding the phenotypic spectrum of the syndrome.

Ophthalmologic involvement in individuals with this condition include hypermetropia, strabismus, congenital cataract, and optic atrophy.

Hearing impairment. A minority of affected individuals experience recurrent otitis media.

Neuroimaging/other neurodevelopmental features

• Brain MRI. Structural brain abnormalities may be universal, including signs of abnormal neuroblast migration and abnormal axonal guidance. Affected individuals have been described as having:
  • Ventriculomegaly
  • Aplasia/hypoplasia of the corpus callosum
  • Hydrocephalus
  • Arnold-Chiari malformation
  • Intraventricular hemorrhage
• Infrequent findings (present in fewer than 10% of reported individuals) may include the following:
  • Sacral dimple
  • Dural ectasia
  • Spina bifida
  • Pineal cyst
  • Cervical spinal canal stenosis

Musculoskeletal. Joint hypermobility is common. Affected individuals may also experience joint dislocations. Other findings can include:

• Long, slender fingers
• Persistence of the fetal fingertip pads
• Hypoplasia of the hand muscles
• Pes planus
• Pes cavus
• Calcaneovalgus deformity
• Congenital hip dislocation
• Scoliosis/kyphosis
• Pectus anomalies, including pectus excavatum or pectus carinatum
• Slender build
• Spondylolisthesis (infrequently)
• Craniosynostosis (infrequently), most commonly sagittal, but metopic has also been observed

Congenital heart defects mainly include septal heart defects; however, cardiac valve disease, aortic root dilatation, and pulmonary stenosis have also been described.

Renal and urologic anomalies include vesicoureteral reflux, hydronephrosis, pyelectasis, and duplex renal system. Cryptorchidism has been reported in the majority of males. A minority of affected individuals experience recurrent urinary tract infection.

Respiratory. Some affected individuals experience recurrent respiratory infections. There is no known immune deficiency described in affected individuals that can explain this finding. Tracheo-/laryngomalacia has also been reported in a relatively small number of affected individuals.

Other associated features reported infrequently (fewer than 10% of known affected individuals)

• Endocrinology. In addition to at least one affected individual with growth hormone deficiency, other reported hormonal issues include hypothyroidism, precocious puberty, and primary adrenal insufficiency.
• Integument. A myriad of skin findings have been described, typically in a few individuals each, including [Wright et al 2011, Zollino et al 2015, Koolen et al 2016]:
  • Multiple nevi
  • Other pigmentary skin abnormalities, such as vitiligo and café au lait macules
  • Hemangioma
  • Eczema
  • Ichthyosis/hyperkeratosis
  • Hair abnormalities, such as fair hair and/or alopecia
• Neoplasia. It is unclear if individuals with this condition have an increased risk above the general population risk of developing a malignancy. Infrequent malignancies in affected individuals have included melanoma and testicular neoplasms. Individuals with KdVS who have lighter skin tones or skin types who are at greater risk for developing melanoma should be evaluated annually to assess ectodermal findings and cutaneous changes (see Management). Currently, there is no consensus tumor screening protocols that have been proposed or published for individuals with KdVS.

Life span. Longitudinal data are insufficient to determine life expectancy, although survival into adulthood is typical. One reported individual is alive at age 63 years [Farnè et al 2022].

Genotype-Phenotype Correlations

Genotype-phenotype correlations in KdVS have not been demonstrated. Notably, the clinical features of affected individuals with atypical deletions and those with pathogenic variants in KANSL1 are in keeping with the phenotype seen in individuals with a classic 17q21.31 deletion [Zollino et al 2015, Koolen et al 2016].

Penetrance

Penetrance is 100%. Clinical features of KdVS are apparent in all individuals with a deletion of or a pathogenic variant in KANSL1, although the extent and severity of clinical findings vary among individuals.

Nomenclature

The disorder was first recognized following chromosomal microarray analysis among large cohorts of unselected individuals with intellectual disability [Koolen et al 2006, Sharp et al 2006, Shaw-Smith et al 2006]. The identification of individuals with a similar phenotype and a de novo KANSL1 pathogenic variant [Koolen et al 2012b, Zollino et al 2012] led OMIM to assign the name "Koolen-de Vries syndrome" to the condition.

Prevalence

The prevalence of KdVS is unknown. The authors estimate the prevalence of the 17q21.31 deletion to be 1:55,000 individuals [Koolen et al 2016]. The prevalence of individuals with a pathogenic sequence variant in KANSL1 cannot be determined with precision owing to the limited number of such affected individuals identified thus far. Preliminary data suggest that pathogenic KANSL1 sequence variants may be as frequent as deletions, but more studies are needed to determine an unbiased prevalence.

Evaluations Following Initial Diagnosis

To establish the clinical consequences in an individual diagnosed with Koolen-de Vries syndrome (KdVS), the evaluations in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for Koolen-de Vries syndrome.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 5).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Table 6 are recommended.

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

Koolen-de Vries syndrome (KdVS), caused by a heterozygous deletion at chromosome 17q21.31 or a heterozygous intragenic KANSL1 pathogenic variant, is an autosomal dominant disorder. Almost all affected individuals represent simplex cases (i.e., a single affected individual in the family).

Risk to Family Members

Parents of a proband

• To date, all reported intragenic KANSL1 pathogenic variants and almost all reported 17q21.31 deletions have been de novo in the proband.
• Evaluation of the parents by testing that will detect the 17q21.31 deletion or intragenic KANSL1 pathogenic variant present in the proband is recommended to confirm their genetic status and to allow reliable recurrence risk counseling. FISH analysis in the parents to evaluate for a balanced insertion and/or translocation may also be considered.
• All unaffected parents tested to date from whom a deleted chromosome 17 originated have shown a 900-kb inversion involving chromosome 17q21.31. This inversion (also referred to as the H2 lineage) is enriched in Europeans, and carriers are predisposed to the 17q21.31 deletion (see Molecular Genetics).
  Note: Testing for the 17q21.31 inversion polymorphism in parents is not recommended for recurrence risk assessment because it does not provide additional information that is of clinical use. The inversion is common in northern European populations, and although it seems to be a necessary factor for the deletion to occur, many other factors are important given the fact that the 17q21.31 deletion is relatively rare.
• If the 17q21.31 deletion or intragenic KANSL1 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 genetic alteration.
  • The proband inherited a genetic alteration from a parent with germline (or somatic and germline) mosaicism. Somatic and (presumed) germline mosaicism for a 17q21.31 deletion has been identified in at least two parents [Koolen et al 2012a].
    Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a genetic alteration that is present in the germ cells only.
• Theoretically, a parent could have a balanced chromosome rearrangement involving 17q21.31 resulting in a 17q21.31 deletion in an affected child; balanced chromosome rearrangements in parents involving 17q21.31 have not been reported to date.

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

• If the parents are clinically unaffected and the 17q21.31 deletion or intragenic KANSL1 pathogenic variant detected in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of:
  • Parental germline mosaicism [Koolen et al 2012a];
  • A balanced chromosome rearrangement involving 17q21.31 (not reported, but theoretically possible).

Offspring of a proband

• Individuals who have the 17q21.31 deletion or an intragenic KANSL1 pathogenic variant have a 50% chance of transmitting the genetic alteration to each child.
• To date, one individual diagnosed with KdVS has been known to reproduce [Author, personal observation].

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has a KdVS-related genetic alteration or, theoretically, a balanced chromosomal rearrangement, 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 parents of a child with KdVS.

Prenatal Testing and Preimplantation Genetic Testing

Once the KdVS-related genetic alteration 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

De novo pathogenic variants in KANSL1 were identified in children with clinical features that are in keeping with the phenotype seen in individuals with a classic 17q21.31 deletion, demonstrating that KANSL1 is the primary gene involved in this deletion syndrome [Koolen et al 2012b, Zollino et al 2012].

KANSL1 encodes KAT8 regulatory NSL complex subunit 1 (KANSL1), the longer isoform of which (NP_001180395.1) has 1,105 amino acids. KANSL1 is a scaffold protein of the nonspecific lethal complex that contains the histone acetyltransferase MOF, which acetylates histone H4 on lysine 16 (H4K16ac) to facilitate transcriptional activation [Mendjan et al 2006].

H4K16ac activates the expression of a broad set of genes including several autophagy-related genes [Füllgrabe et al 2013]. Autophagy is a catabolic process important for the clearance of protein aggregates and damaged organelles within the cell, which is essential for cell homeostasis and survival. Autophagy is essential in neurons, not only for cell homeostasis but also for regulation of development and function [Shehata et al 2012, Tang et al 2014].

Studies in mice have shown that heterozygous loss of Kansl1 leads to changes in gene expression related to synaptic transmission and to a decrease in basal synaptic transmission and plasticity [Arbogast et al 2017], but the underlying cellular mechanisms remain unknown.

Linda et al [2022] reported that KANSL1 deficiency leads to increased oxidative stress and autophagosome formation in iPSCs and iNeurons. In neurons, increased reactive oxygen species (ROS)-activated autophagy reduced neuronal synaptic connectivity and activity. The observed neuronal phenotype could be rescued by treatment with apocynin, an antioxidant that reduced oxidative stress and autophagosome accumulation. These findings were supported by the study of Li et al [2022], in which KANSL1 was identified as an essential gene for autophagy using siRNA screening. Kansl1^+/- mice exhibit impairment in the autophagic clearance of damaged mitochondria and accumulation of reactive oxygen species, thereby resulting in defective neuronal and cardiac function.

Laboratory technical considerations. Genetic testing of the 17q21.31 genomic region is challenging. The mapping and interpretation of the deletion breakpoints are confounded by the structural complexity and genomic variation of the 17q21.31 locus [Koolen et al 2016]. Two haplotypes exist, in direct (H1) and inverted (H2) orientation [Stefansson et al 2005]. The H2 haplotype is enriched in Europeans, and those with this haplotype are predisposed to the 17q21.31 deletion [Koolen et al 2006, Sharp et al 2006, Koolen et al 2008, Zody et al 2008]. However, the frequency of de novo 17q21.31 deletions in those with the H2 inversion is low, and other as yet poorly understood factors are likely to be important in the generation of the deletion.

The 17q21.31 inversion polymorphism (H2 haplotype) and the copy number polymorphism clusters encompassing exons 1-3 of KANSL1 contribute to difficulties in single nucleotide variant calling, such as loss-of-function variant "artifacts" in KANSL1 [Koolen et al 2016]. The detection of a truncating variant in exons 1-3 of KANSL1 is not sufficient to make a diagnosis of KdVS. In these cases, a compatible clinical phenotype and variant analysis of parental samples is of the utmost importance to verify that the possibly pathogenic variant occurred de novo.

Mechanism of disease causation. Loss of function. The 17q21.31 deletion is typically 500 to 650 kb in size (hg19: chr17:43,700,000-44,250,000) and is flanked by segmental duplications that mediate nonallelic homologous recombination [Itsara et al 2012].

Author Notes

Radboudumc Center of Expertise: rare congenital developmental disorders

Acknowledgments

The authors gratefully acknowledge the KdVS Foundation, other support groups and the parents/caregivers for their participation in research and for their generous sharing of information.

Revision History

• 2 February 2023 (ma) Comprehensive update posted live
• 13 June 2019 (ma) Comprehensive update posted live
• 10 January 2013 (cd) Revision: sequence analysis of KANSL1 available clinically
• 20 November 2012 (me) Comprehensive update posted live
• 26 January 2010 (me) Review posted live
• 28 August 2009 (dak) Original submission

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