Kleefstra syndrome (KLEFS1) has characteristic but not always specific features, and can overlap clinically with other neurodevelopmental disorders. Genotype-phenotype patterns have emerged: individuals with larger, multigene deletions tend to have more significant intellectual disability and higher rates of constipation and short stature, while those with a single-gene EHMT1 variant often have milder features overall.

Once an EHMT1 variant is identified, counseling should cover the condition and its genetic cause, inheritance pattern, recurrence risk, and reproductive options, as well as available therapeutic options and the range of ways KS can present. Clinicians should proactively share information about patient advocacy groups, peer support, and reliable resources, and regularly check in on the emotional wellbeing of the whole family — not just the diagnosis itself.

1. Refer anyone with features suggestive of Kleefstra syndrome — whether flagged by a clinician or by parent concern — for evaluation and genetic testing.
2. Perform genome sequencing (or exome sequencing if genome sequencing isn’t accessible), ideally as a trio with both parents, as the first test. If that’s non-diagnostic, follow with chromosomal microarray (or the reverse order if microarray comes first).
3. Refer anyone with a pathogenic or uncertain (VUS) EHMT1 variant to a clinical genetics team — or a clinician specialized in genetic neurodevelopmental conditions if one isn’t available — for phenotype evaluation, diagnosis confirmation, and counseling.
4. For individuals with a known 9q34.3 deletion, offer karyotyping and FISH testing (or long-read sequencing) for both parents to check for a balanced structural variant and estimate recurrence risk.
5. Consider gene-targeted copy number variant analysis for individuals whose standard testing was non-diagnostic but clinical suspicion for KS remains high, since small structural variants can be missed.
6. Consider additional specialized testing (e.g., DNA methylation signature) or enrollment in research studies when features strongly suggest KS but testing — including EHMT1 VUS results — hasn’t confirmed it.

Behavioral issues often show up in childhood, while diagnosable mental health conditions more often emerge in adolescence and adulthood; autism spectrum disorder affects the majority of people with KS. Because symptoms and needs shift over time, annual screening in primary or pediatric care is recommended — including medication review, related conditions like constipation or regression, and current supports in place. Physical causes (like thyroid problems or vitamin deficiencies) should also be considered as possible contributors to psychiatric symptoms.

Recommended tools for assessing intellectual disability, developmental delay, and mental health symptoms in KS include the Vineland Adaptive Behavior Scales, Mini PAS-ADD, Autism Diagnostic Observation Schedule, Child Behavior Checklist, and standard IQ testing.

1. Review behavior and mental health at diagnosis and annually thereafter, factoring in medication, co-occurring conditions, and current supports.
2. Refer for further evaluation by the right professional when behavior or mental health concerns arise, for diagnosis and/or intervention.
3. Proactively refer to psychiatric or psychological care when symptoms suggest a condition causing real functional impairment.
4. Use personalized, behavior-principle-based interventions grounded in a functional assessment as the primary approach.
5. Proactively evaluate and act on any sudden emergence of new behaviors or mental health symptoms, or significant changes.

Regression is defined as an absolute decline in functioning — in practical, conceptual, or social-emotional skills — that would last several months if left untreated. Episodes may be preceded by severe sleep problems or by physical or emotional stressors (like an illness, a move, or a loss). Speech-language, motor, social-emotional, and cognitive skills can all decline, often together with aggressive outbursts, temper tantrums, and worsening sleep.

A full work-up should include psychiatric evaluation as well as neurological and pediatric assessment to rule out treatable medical causes, and to distinguish regression from psychosis or catatonia (which need different treatment). Among medications, olanzapine has shown the most consistent effectiveness; aripiprazole and risperidone/haloperidol combinations have helped in some cases but carry more risk of side effects. Benzodiazepines are generally not effective for regression (and can cause paradoxical agitation) — except in true catatonia, where they remain first-line.

1. Urgently refer anyone with suspected regression to an experienced clinician for assessment, diagnosis, and treatment.
2. Use standardized instruments to measure and track adaptive functioning over time.
3. Consider olanzapine, in consultation with a psychiatrist, for new or ongoing regression — especially with psychosis or severe insomnia. Catatonia may need a different treatment path.
4. Contact a specialized Kleefstra syndrome center for further evaluation, management support, and collaborative data collection.

Structural brain differences show up in roughly half of individuals with KS — things like white matter changes, mild ventricle enlargement, or cerebellar/brainstem differences — but most are non-specific and don’t require intervention on their own. Seizure onset can occur from infancy through adolescence, most commonly focal or tonic-clonic; earlier onset (before 36 months) tends to mean more frequent seizures. Valproic acid and carbamazepine have shown effectiveness; levetiracetam is a common first-line option but can worsen behavioral irritability in some individuals, so it should be used thoughtfully.

1. Consider a brain MRI at diagnosis when clinically indicated (focal seizures, abnormal EEG, regression, or sudden psychosis/catatonia); consider gadolinium contrast as indicated.
2. Consider a follow-up MRI for actionable prior findings or new clinical changes.
3. Refer to a neurologist or epilepsy specialist for suspected or confirmed seizures; treat per local protocol.
4. Get a routine EEG (with video, awake and asleep) as an initial assessment when seizures or regression are a concern, with follow-up EEG for new seizure patterns.
5. Wean antiseizure medications per local protocol, but consider continuing longer if epilepsy has been severe or hard to control, or based on shared decision-making with the family.

Insomnia (trouble falling or staying asleep) is the most common sleep issue in KS; sleep apnea and motor restlessness during sleep occur less often but do happen. Sleep problems often travel together with anxiety, sensory processing differences, and possible disruption to the circadian rhythm. Managing underlying psychiatric symptoms can improve sleep, and vice versa.

When treatment is needed, slow-release melatonin — alone or combined with quetiapine or trazodone — has shown the most consistent benefit for insomnia, though some individuals do have paradoxical reactions. For sleep apnea, positional therapy or positive airway pressure are recommended. Benzodiazepines have inconsistent results and can also cause paradoxical effects.

1. Review sleep regularly at every age; discuss monitoring strategies (like sleep diaries) with caregivers.
2. Recommend sleep hygiene strategies tailored to neurodevelopmental conditions, and adapt daily/bedtime routines to the individual’s sensory profile.
3. Evaluate medical, psychiatric, social, and environmental contributors to sleep problems.
4. Proactively refer to a sleep specialist when poor sleep is reported.
5. Be alert to paradoxical reactions to sleep medications (benzodiazepines, melatonin); discourage unsupervised use.
6. Treat sudden, severe changes in sleep from puberty onward with the same urgency described in the Regression section.

Both conductive and sensorineural hearing loss occur in KS, most often mild and bilateral, though it can appear at any age and sometimes progresses over time independent of regression. Recurrent ear infections and cerumen (earwax) impaction — likely related to narrow ear canals in KS — are common contributors to conductive hearing loss, so early, proactive management matters.

1. Perform audiological assessment at diagnosis, annually until age 6, then every 2 years until early adolescence — more often if clinically indicated.
2. Perform audiological assessment in adults following intellectual-disability guidelines.
3. Prevent build-up of earwax.
4. Proactively manage ear infections and fluid to minimize discomfort, prevent hearing loss, and support development.
5. Apply hearing (and vision) interventions tailored to developmental age, behavior, sensory processing, and tactile sensitivity.

Refractive abnormalities tend to show up early in life, while strabismus can be diagnosed at any age. Some individuals with KS have or are suspected to have cerebral visual impairment (CVI), possibly related to complications from cardiac surgery or severe seizures — this affects how the brain processes what the eyes see, not just how the eyes themselves work.

1. Refer to an ophthalmologist at diagnosis and whenever concerns arise, paying particular attention to strabismus, refractive errors (especially hypermetropia), and cerebral visual impairment.
2. Assess visual acuity regularly per local protocol, with extra attention to strabismus under age 6; adults should follow intellectual-disability guidelines.
3. Manage vision conditions per local protocol, referring to specialists (low-vision rehab, OT, psychology) as needed for adaptive strategies and assistive devices.

About 65% of individuals with KS age 3 and older can form sentences, with first words typically appearing after age 2; larger chromosomal deletions tend to mean more significant speech and language impact than smaller or single-gene variants. Nearly all verbal individuals (98%) have at least one speech disorder — most commonly dysarthria or childhood apraxia of speech — and speech ability is often noticeably behind cognition and language comprehension.

AAC is a broad term covering everything from sign language to high-tech communication devices, and importantly, using AAC does not impede or delay speech development — it supports it. Interventions developed for autism and other genetic conditions may also be beneficial for individuals with KS.

1. Assess speech and language at diagnosis and at least annually until age 12, by a speech therapist.
2. Assess speech and language in adolescents and adults as needed — for example, after a regressive episode — to set or update therapy goals.
3. Perform an AAC evaluation if speech alone can’t meet all everyday communication needs.
4. Provide therapy tailored to the individual’s specific speech and language diagnoses, including sign/gesture and AAC where indicated.
5. Adapt AAC to the individual’s cognitive, vision, hearing, and co-occurring conditions (like autism or sensory processing disorder).

KS is associated with a range of congenital and acquired heart conditions, including septal and valve defects and rhythm disturbances — the latter particularly diagnosed in late adolescence. Most congenital heart findings reported have not been clinically significant and haven’t required major intervention, though more serious malformations requiring surgery do occur in some cases. When rhythm abnormalities are present, individuals with KS respond well to the same treatments used in the general population.

If there’s an unexplained decline in thinking, mood, or overall function, cardiac issues should be considered as part of the picture — not just neurological or psychiatric causes. Regular monitoring of weight and metabolism also helps reduce cardiovascular risk (see Growth & Metabolism).

1. Refer to a cardiologist at diagnosis for evaluation of congenital heart defects (echocardiogram or cardiac MRI) and rhythm abnormalities (ECG).
2. Consult a cardiologist before starting new medications with potential cardiac effects (psychiatric, prokinetic, certain neurological drugs).
3. Manage structural heart defects and/or rhythm abnormalities per local protocol.
4. Starting at age 18, perform an annual screening ECG in all individuals with KS.
5. Urgently refer to a cardiologist for ECG abnormalities or new/worsening cardiorespiratory symptoms.
6. Consider repeat imaging, ECGs, or longer-term rhythm monitoring for new or worsening symptoms, or unexplained decline in thinking, mood, or function.

Short stature affects a minority of individuals with KS, usually without a specific underlying cause; overweight and obesity, however, affect the majority, and may relate to how EHMT1 loss-of-function disrupts fat metabolism. Contributing risk factors can include reduced motivation to be active, overeating, psychotropic medication side effects, and hypothyroidism. Head circumference tends to run smaller than average across all ages, with roughly half of adults meeting criteria for microcephaly.

1. Measure height and weight regularly in childhood/adolescence using appropriate growth and target-height charts; measure head circumference at least until age 3. In adulthood, assess weight, waist circumference, and BMI at least yearly.
2. Perform a diagnostic work-up (e.g., growth hormone, thyroid function, bone age) if short stature and/or overweight is present.
3. Offer guidance on healthy lifestyle habits; consider referral to a dietitian/nutritionist, especially for those who are overweight or on psychotropic medications.
4. Evaluate thyroid function at puberty onset and as clinically indicated; monitor for (pre)diabetes in adolescents and adults.
5. Evaluate bone density at puberty onset and after unexplained fractures; consider vitamin D supplementation, especially with limited sun exposure.

Constipation in KS ranges from mild to severe (occasionally requiring surgery) and is multifactorial — common contributing factors include low muscle tone, delayed toilet training, low fluid intake, dietary restrictions, constipating medications, reduced activity, and hypothyroidism. Left unaddressed, it can seriously affect mental health, sleep, and increase the risk of urinary tract infections.

1. Evaluate for constipation at all ages through careful history and physical exam.
2. Stay alert to new or worsening constipation, which can present atypically — especially alongside increased behavioral, sleep, or psychiatric symptoms.
3. Watch for symptoms suggesting an underlying contributing factor; consider labs including thyroid function.
4. Recommend increased fluid and fiber intake, physical activity, and healthy toileting habits to prevent and treat constipation.
5. Treat per local protocol (typically volume-increasing laxatives like macrogol or psyllium), unless there’s an aspiration risk.
6. Refer to a gastroenterologist if constipation persists despite standard therapy.

This chapter reflects direct input from parents of individuals with Kleefstra syndrome who took part in the guideline consensus process. It calls on providers to be open to what families bring to appointments — their own observations, questions, and expertise — and to proactively connect families with data registries and natural history studies, financial assistance, educational resources, disability supports, and respite care.

1. Offer timely, clear, honest, accessible explanations about the cause of the condition, recommended health checks, and the natural history of KS.
2. Provide information aligned to each family’s preferences, concerns, and coping style, with follow-up appointments across the lifespan.
3. Provide details on patient advocacy/peer-support organizations, counseling services, and reliable information sources.
4. Ask about emotional wellbeing — including siblings and grandparents — at every appointment, and offer appropriate support.
5. Consult with KS experts and expert centers when needed.
6. Be open to the information and observations that families and support providers bring to appointments.
7. Link families to opportunities to participate in data registries and natural history studies.
8. Support families in accessing financial assistance, educational resources, disability supports, and respite services.
9. Proactively discuss a transition-to-adult-care plan, starting in mid-adolescence.
10. Link families, where possible, to a multidisciplinary clinic and/or care coordinator.