How is Luscan-Lumish syndrome inherited?

Luscan-Lumish syndrome follows an autosomal dominant inheritance pattern. This means inheriting just one copy of the altered gene from either parent can cause the condition.

How rare is Luscan-Lumish syndrome?

Luscan-Lumish syndrome is classified as very rare. The estimated prevalence is approximately <1 in 1,000,000. Because rare disease data can be limited, actual numbers may differ from published estimates.

How is Luscan-Lumish syndrome diagnosed?

Information about diagnosis is currently limited for this condition.

Are there treatments for Luscan-Lumish syndrome?

Information about treatment is currently limited for this condition.

What complications might arise from Luscan-Lumish syndrome?

Currently, there is limited information about the specific complications associated with Luscan-Lumish syndrome. Because this condition is rare and not well understood, ongoing research is needed to identify any potential complications that may arise as individuals grow older. It is important for families to stay in touch with healthcare providers for updates as more information becomes available.

How might Luscan-Lumish syndrome affect daily life?

Details about how Luscan-Lumish syndrome impacts daily life are not fully known at this time. Families may find that the condition affects various aspects of life, including physical activities or social interactions, depending on the symptoms present. It is essential for families to work closely with healthcare providers to create supportive environments for those affected.

What is the prognosis for someone with Luscan-Lumish syndrome?

Information about the prognosis for individuals with Luscan-Lumish syndrome is currently limited. Since this condition is rare and not well understood, it is difficult to predict how it may progress over time. Families are encouraged to consult with medical professionals for guidance and to stay informed as research continues.

Are there any specialists recommended for managing Luscan-Lumish syndrome?

At this time, there are no specific specialists mentioned for managing Luscan-Lumish syndrome due to the limited information available. However, families may benefit from consulting with geneticists or specialists in rare diseases who can provide support and guidance. It is important to have a healthcare team that understands the complexities of rare conditions.

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Luscan-Lumish syndrome (LLS) - Clinical Profile, Genes & Research | Kisho | Kisho

Rare Disease

Luscan-Lumish syndrome

MONDO:0014791

Also known as:LLSLuscan-Lumish syndrome; LLsSETD2-related overgrowth syndrome

Overview

GeneticsAutosomal dominant · SETD2 (chr 3)

ResearchLimited published research (6 articles)

Clinical Presentation

Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.

Features include: Short stature, Seizure, Syringomyelia, and Slurred speech and 29 more.

Organ System	Phenotype Count	Example Features
Brain and nerves	9	Seizure, Slurred speech, Aggressive behavior
Head and neck

Genetic Landscape

Assembled from HGNC gene records, ClinGen gene-disease validity evidence, and ClinVar pathogenic variant data. Validity classifications reflect the strength of published evidence linking each gene to this disease.

SETD2 function has not been fully characterized.

Luscan-Lumish syndrome is associated with mutations in the SETD2 gene on chromosome 3.

GeneReviews

Clinical Guidance

SETD2-NDD with normal growth and without macrocephaly. The variant is the only SETD2 pathogenic variant known to be associated with this phenotype . Features of the three individuals with this finding include the following:

Diagnosis

Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.

GeneReviews

Diagnostic Criteria

No consensus clinical diagnostic criteria for SETD2 neurodevelopmental disorders (SETD2-NDDs) have been published. SETD2-NDD represents a clinical spectrum with the most common well-defined phenotype being SETD2-NDD with macrocephaly/overgrowth, although not everyone has overgrowth; a specific, somewhat different phenotype has been reported in association with a particular pathogenic variant, c.5218CT (p.Arg1740Trp), which leads to a higher frequency of multiple congenital anomalies (MCA) compared to those without this genetic change . This chapter covers both of these recognized phenotypes.

Suggestive Findings

Treatment

Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.

No approved treatments are currently available for Luscan-Lumish syndrome. The disease remains an area of unmet medical need.

GeneReviews

Management Guidelines

No clinical practice guidelines for SETD2 neurodevelopmental disorders have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with SETD2 neurodevelopmental disorders (SETD2-NDD), the evaluations summarized (SETD2-NDD w/or w/o macrocephaly/overgrowth) and (SETD2-NDD w/MCA) if not performed as part of the evaluation that led to the diagnosis are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis: SETD2-NDD with or without Macrocephaly/Overgrowth

Prognosis

Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.

GeneReviews

Surveillance Guidelines

and summarize the recommended surveillance for individuals with SETD2-NDD with or without macrocephaly/overgrowth and those with SETD2-NDD with MCA, respectively. Table 9. Recommended Surveillance for Individuals with SETD2-NDD with or without Macrocephaly/Overgrowth

Research Landscape

Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.

No clinical trials have been registered for Luscan-Lumish syndrome.

6 publications have been identified in PubMed for Luscan-Lumish syndrome. Research spans Case Report / Case Series (83%) and Basic Science / Preclinical (17%).

Recent Publications

Ünsel-Bolat G (2026). [PMID: 41466099](https://pubmed.ncbi.nlm.nih.gov/41466099/). *Dev Neurobiol*. [Case Report / Case Series]
Lucain M (2025). [PMID: 40104911](https://pubmed.ncbi.nlm.nih.gov/40104911/). *Am J Med Genet A*. [Case Report / Case Series]
Romano F (2025). [PMID: 39907171](https://pubmed.ncbi.nlm.nih.gov/39907171/). *Birth Defects Res*. [Case Report / Case Series]
Wójcik-Niklewska B (2025). [PMID: 40574928](https://pubmed.ncbi.nlm.nih.gov/40574928/). *World J Clin Cases*. [Case Report / Case Series]
Atterton C (2025). [PMID: 41023182](https://pubmed.ncbi.nlm.nih.gov/41023182/). *Sci Rep*. [Basic Science / Preclinical]
Orozco-Fernández M (2025). [PMID: 40892041](https://pubmed.ncbi.nlm.nih.gov/40892041/). *J Craniofac Surg*. [Case Report / Case Series]

Data assembled from 7 of 12 sources · Last updated Sep 18, 2026, 4:35 PM UTC

MONDOHPOClinicalTrials.govFDAPubMedHGNCClinVarClinGenGeneReviewsOrphanetOMIMRUSP

Medical References

External Resources

OMIM

Online Mendelian Inheritance in Man

OMIM:616831

Orphanet

European rare disease database

Orphanet:597738

GARD

Genetic and Rare Diseases Info Center

GARD:13789

Questions for Your Care Team

→Should I pursue genetic testing for SETD2, and what would the results mean for my family?
→Are there specialists or centers of excellence for this condition in my area?
→Is there a patient registry I should consider joining?

FAQ

Frequently Asked Questions

Common questions about Luscan-Lumish syndrome

Luscan-Lumish syndrome is a rare condition that has been identified through genetic studies and is associated with changes in the SETD2 gene. The condition is also known by several names including LLS, LLs, and SETD2-related overgrowth syndrome. It is recognized in medical literature by identifiers such as OMIM:616831, Orphanet:597738, and GARD:13789. Because detailed descriptions and definitions are not available in the provided sources, much about the overall presentation and natural history of Luscan-Lumish syndrome remains unknown. Ongoing research and future studies will hopefully provide more information about how this condition develops and affects those living with it.

Information about symptoms is currently limited for this condition.

Luscan-Lumish syndrome is linked to changes in the SETD2 gene. This genetic alteration is considered to be a key factor in the development of the condition. However, detailed descriptions of how the genetic changes lead to the full range of features associated with Luscan-Lumish syndrome are currently limited. Associated genes include SETD2.

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GeneReviews

Clinical Guidance

To date, 30 individuals have been reported with a SETD2 pathogenic variant, excluding those who have deletions of the 3p21.31 region that includes SETD2 and other adjacent genes [, , , , , , , , ]. SETD2 neurodevelopmental disorder (SETD2-NDD) with macrocephaly/overgrowth, the most common phenotype, can also include developmental delay / intellectual disability, obesity, advanced bone age, and behavioral findings (most typically an autism spectrum disorder). This spectrum also includes three individuals (2 male and 1 female) with a heterozygous pathogenic SETD2 variant who have normal growth . SETD2-NDD with multiple congenital anomalies (MCA) presents with microcephaly, brain malformations, profound intellectual disability, severe failure to thrive, and multiple congenital anomalies including congenital heart defects, urogenital anomalies, and ophthalmic findings such as Coats disease of the retina. These individuals have a pathogenic SETD2 variant . Table 2. SETD2 Neurodevelopmental Disorders: Phenotypes by Selected Distinguishing Features

Feature	SETD2-NDD with or without Macrocephaly/Overgrowth1	SETD2-NDD with MCA (c.5218CT pathogenic variant)
# of reported persons	18	12
Macrocephaly (incl relative macrocephaly)	12/17	0
Intellectual disability	14/18 (typically in moderate range)	12/12 (typically in profound range)
Overgrowth /or obesity	9/18	0
Advanced bone age	5/6 examined	1/1 person examined
Autism spectrum disorder	10/13	0
Microcephaly	0	12/122
Failure to thrive in infancy3	0	12/12
Hypotonia	5/8	12/12
Seizures	3/18	7/12
Brain malformations	7/11 examined	12/12
Ophthalmologic	4/6 examined	10/10 examined
Hearing loss (conductive or mixed)	1/2 examined	7/9
Skeletal abnormalities	5/7	12/12
Congenital heart defects	1/3 reported	11/12
Urogenital anomalies	2/2 reported	11/12 Data from , , , , , , , , MCA = multiple congenital anomalies; NDD = neurodevelopmental disorder 1. This column also includes those individuals with a heterozygous c.5219GA (p.Arg1740Gln) pathogenic variant in SETD2. 2.

Source: GeneReviews — "SETD2 Neurodevelopmental Disorders"

GeneReviews

Differential Diagnosis

Because the phenotypic features associated with SETD2 neurodevelopmental disorder (SETD2-NDD) without macrocephaly/overgrowth or multiple congenital anomalies (MCA) are not sufficient to diagnose this condition, all disorders with intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM Autosomal Dominant, Autosomal Recessive, Nonsyndromic X-Linked, and Syndromic X-Linked Intellectual Developmental Disorder Phenotypic Series. For the differential diagnosis of SETD2-NDD with macrocephaly/overgrowth, see . For the differential diagnosis of SETD2-NDD with MCA, see . Table 3. Differential Diagnosis of SETD2-NDD with Macrocephaly/Overgrowth

Gene(s)	DiffDx Disorder	MOI	Clinical Features of DiffDx Disorder
FMR1	Fragile X syndrome (See FMR1 Disorders.)	XL	Macrocephaly, ID
Sotos syndrome	AD	Macrocephaly, overgrowth, ID	Pointed chin, small mouth, everted lower lip NFIX
Beckwith-Wiedemann syndrome	AD1	Generalized overgrowth, DD	Macroglossia, hypoglycemia, coarse facies, hepatomegaly, ear lobe creases
RNF125	Tenorio syndrome (OMIM 616260)	AD	Macrocephaly, overgrowth, ID
DICER1	GLOW syndrome (See DICER1 Tumor Predisposition.)	AD	Macrocephaly, overgrowth, ID
HERC1	MDFPMR (OMIM 617011)	AR	Macrocephaly, overgrowth, ID
PIK3CA	Megalencephaly-capillary malformation-polymicrogyria syndrome (See PIK3CA-Related Overgrowth Spectrum.)	Somatic	Macrocephaly, overgrowth, ID
PTEN hamartoma tumor syndrome	AD	Macrocephaly, autism	Hamartomata, tumors TET3
Beck-Fahrner syndrome	ADAR	Macrocephaly, overgrowth, ID	Elongated myopathic facies; short stature microcephaly in some
FIBP	Thauvin-Robinet-Faivre syndrome (OMIM 617107)	AR	Macrocephaly, overgrowth, ID
SUZ12	Imagawa-Matsumoto syndrome (OMIM 618786)	AD	Macrocephaly, overgrowth, ID
Costello syndrome	AD	Macrocephaly, ID	Fetal overgrowth w/postnatal short stature, coarse facial features, loose redundant skin
EED	Cohen-Gibson syndrome (See EED-Related Overgrowth.)	AD	Macrocephaly, overgrowth, ID
Simpson-Golabi-Behmel syndrome	XL	Macrocephaly, overgrowth, ID	Coarse facies; hearing loss; large liver, spleen, kidneys; skeletal anomalies ...

Source: GeneReviews — "SETD2 Neurodevelopmental Disorders"

System/Concern	Evaluation	Comment
Constitutional	Measurement of height, weight, head circumference	To assess for overgrowth /or obesity
Development	Developmental assessment	Incl motor, adaptive, cognitive, speech-language eval; Eval for early intervention / special education Neurobehavioral/
Psychiatric	Neuropsychiatric eval	Persons age 12 mos: screen for concerns incl sleep disturbances, ADHD, anxiety, /or traits suggestive of ASD.
Neurologic	Neurologic eval	Incl brain MRI; Consider EEG if seizures are a concern.
Endocrinologic	TSH free T4	To screen for hypothyroidism Clinical eval for signs symptoms of precocious puberty
Musculoskeletal	Orthopedics / physical medicine rehab / PT/OT eval	Incl assessment of:; Gross motor fine motor skills; Mobility, ADL, need for adaptive devices; Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills)
Eyes	Ophthalmologic exam	Incl assessment of visual acuity strabismus
Hearing	Audiologic eval	Assess for sensorineural /or conductive hearing loss.
Cardiovascular	Echocardiogram	To assess for structural heart defects
Genitourinary	Physical exam for cryptorchidism in males	Consult w/urologist as needed. Genetic
counseling	By genetics professionals1	To obtain a pedigree inform affected persons their families re nature, MOI, implications of SETD2-NDD to facilitate medical personal decision making Family support resources
System/Concern	Evaluation	Comment
Constitutional	Measurement of height, weight, head circumference	To assess for FTT in infants
Gastrointestinal	Gastroenterology/ nutrition/ feeding team eval	Incl eval of aspiration risk nutritional status.; Consider eval for gastrostomy tube placement in those w/dysphagia /or aspiration risk.
Respiratory	Assess for signs symptoms of hypoventilation /or tracheomalacia.	Consider referral to pulmonologist.
Development	Developmental assessment	Incl motor, adaptive, cognitive, speech-language eval; Eval for early intervention/ special education
Neurologic	Neurologic eval	Incl brain MRI; Consider EEG if seizures are a concern.
Hearing	Audiologic eval	Assess for sensorineural /or conductive hearing loss.
Eyes	Ophthalmologic exam	Incl assessment of visual acuity, slit lamp exam (for cataracts), fundus exam (for optic nerve hypoplasia, retinal telangiectasia, retinal detachment)
Cardiovascular	Echocardiogram	For congenital heart defects
Genitourinary	Physical exam for cryptorchidism in males	Consider referral to urologist. Kidney ultrasound exam
Endocrinologic	Electrolyte panel1	To assess for hyponatremia; If present, consider eval for SIADH.2 TSH free T4
Musculoskeletal	Orthopedics/ physical medicine rehab/ PT OT eval	Incl assessment of:; Gross motor fine motor skills; Contractures, clubfoot, kyphoscoliosis; Mobility, ADL, need for adaptive devices; Need for PT (to improve gross motor skills) /or OT (to improve fine motor skills) Genetic
counseling	By genetics professionals3	To obtain a pedigree inform affected persons their families re nature, MOI, implications of SETD2-NDD to facilitate medical personal decision making Family...

Kisho

Luscan-Lumish syndrome

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Questions for Your Care Team

Questions for Your Care Team

FAQ

Frequently Asked Questions

Clinical Guidance

Explore clinical features

Differential Diagnosis

Therapies Under Investigation

Clinical Trials

Luscan-Lumish syndrome

Overview

Clinical Presentation

Genetic Landscape

Clinical Guidance

Diagnosis

Diagnostic Criteria

Suggestive Findings

Treatment

Management Guidelines

Prognosis

Surveillance Guidelines

Research Landscape

Recent Publications

Medical References

External Resources

OMIM

Orphanet

GARD

Related Diseases

Questions for Your Care Team

Questions for Your Care Team

FAQ

Frequently Asked Questions

What is Luscan-Lumish syndrome?

What are the symptoms of Luscan-Lumish syndrome?

What causes Luscan-Lumish syndrome?

How is Luscan-Lumish syndrome inherited?

How rare is Luscan-Lumish syndrome?

How is Luscan-Lumish syndrome diagnosed?

Are there treatments for Luscan-Lumish syndrome?

What complications might arise from Luscan-Lumish syndrome?

How might Luscan-Lumish syndrome affect daily life?

What is the prognosis for someone with Luscan-Lumish syndrome?

Are there any specialists recommended for managing Luscan-Lumish syndrome?

Clinical Guidance

Explore clinical features

Differential Diagnosis

Therapies Under Investigation

Clinical Trials