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Houge-Janssens Syndrome

Mendelian MONDO:0957553 Neurodevelopmental disorder PP2A-related disorder

Houge-Janssens syndrome (HJS) is a group of neurodevelopmental disorders caused by dysfunction of protein phosphatase type 2A (PP2A). PP2A is a heterotrimeric serine/threonine phosphatase composed of a catalytic (C), scaffolding (A), and regulatory (B) subunit. PP2A opposes the activity of growth-promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Core clinical features include neurodevelopmental delay (especially affecting language), prolonged hypotonia, high risk of seizures, behavioral problems, and variable head circumference abnormalities. Four subtypes are recognized based on the affected PP2A subunit gene: HJS type 1 (PPP2R5D), HJS type 2 (PPP2R1A), HJS type 3 (PPP2CA), and HJS type 4 (PPP2R5C). Most pathogenic variants are de novo heterozygous missense changes acting through dominant-negative mechanisms.

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Mappings
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Definitions
1
Inheritance
4
Pathophysiology
0
Histopathology
11
Phenotypes
4
Genes
3
Treatments
4
Subtypes
5
Differentials
0
Datasets
0
Trials
🏷

Classifications

Harrison's Chapter
nervous system disorder hereditary disease
Mechanistic Nosology
RASopathy
👪

Inheritance

1
Autosomal dominant HP:0000006
Houge-Janssens syndrome follows autosomal dominant inheritance. Nearly all pathogenic variants arise de novo as heterozygous missense changes.
Autosomal dominant inheritance Penetrance: COMPLETE
Show evidence (1 reference)
PMID:40555839 SUPPORT Human Clinical
"recurrent pathogenic de novo missense variants in several PP2A subunits, some of which are associated with macrocephaly if congenital, or cancer if somatic."
Overview confirms de novo dominant variants across PP2A subunits.
◆

Subtypes

4
Houge-Janssens syndrome type 1 (PPP2R5D)
Most well-characterized subtype, caused by de novo missense variants in PPP2R5D encoding the B56delta regulatory subunit. Features include macrocephaly, developmental delay, intellectual disability, seizures, ASD, and early-onset parkinsonism. Recurrent variants include E198K and E420K.
Show evidence (2 references)
PMID:40555839 SUPPORT Human Clinical
"dominant pathogenic variants in at least two B subunits (PPP2R5D in HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause Houge-Janssens syndrome."
Overview paper defining HJS type 1 as PPP2R5D-related.
PMID:39201832 SUPPORT Human Clinical
"NDDs related to the PPP2R5D gene have recently been defined as Houge-Janssens syndrome 1."
Confirms PPP2R5D as the gene causing HJS type 1.
Houge-Janssens syndrome type 2 (PPP2R1A) Not Yet Curated MONDO:0014605
Caused by de novo missense variants in PPP2R1A encoding the Aalpha scaffolding subunit. Recurrent hotspots include p.Arg182Trp and p.Arg183Gln in HEAT repeats 5-7. Developmental delay and intellectual disability are universal. Epilepsy occurs in ~51% and structural brain abnormalities in ~83%, with corpus callosum abnormalities and ventriculomegaly most frequent.
Show evidence (2 references)
PMID:41465181 SUPPORT Human Clinical
"We identified 16 studies representing 60 patients with PPP2R1A-related disorders. Twenty-six distinct pathogenic variants were identified; these were predominantly de novo heterozygous missense changes clustering within HEAT repeats 5-7."
Systematic review of 60 PPP2R1A patients defining the clinical spectrum of HJS type 2.
PMID:40781915 SUPPORT Human Clinical
"Houge-Janssens syndrome type 2 (HJS2, OMIM 616362) is a rare neurodevelopmental disorder caused by pathogenic variants in PPP2R1A, typically characterized postnatally by hypotonia, developmental delay, intellectual disability, and distinctive craniofacial features."
Case report confirming HJS2 phenotype including prenatal features.
Houge-Janssens syndrome type 3 (PPP2CA) Not Yet Curated MONDO:0032697
Caused by de novo missense and loss-of-function variants in PPP2CA encoding the Calpha catalytic subunit.
Show evidence (1 reference)
PMID:40555839 SUPPORT Human Clinical
"dominant pathogenic variants in at least two B subunits (PPP2R5D in HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause Houge-Janssens syndrome."
Overview defines HJS type 3 as PPP2CA-related.
Houge-Janssens syndrome type 4 (PPP2R5C) Not Yet Curated MONDO:0978293
Caused by de novo missense variants in PPP2R5C encoding the B56gamma regulatory subunit. Clinical features are within the HJS spectrum with strongest resemblance to HJS type 1. Average intellectual disability is milder than other subtypes. Head circumferences are above average or macrocephalic. Pathogenic mechanism is dominant-negative on substrate dephosphorylation.
Show evidence (1 reference)
PMID:39978342 SUPPORT Human Clinical
"The clinical features were well within the HJS spectrum with strongest resemblance to HJS type 1, caused by B56delta variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features."
Defines HJS type 4 clinical spectrum in 26 individuals with PPP2R5C variants.
⚙

Pathophysiology

4
PP2A subunit mutations
De novo dominant missense variants in PP2A subunit genes (PPP2R5D, PPP2R1A, PPP2CA, PPP2R5C) disrupt the structure or function of the affected subunit. In PPP2R5D, variants such as E198K and E420K cause dominant-negative effects rather than loss of function.
PPP2R5D link PPP2R1A link PPP2CA link PPP2R5C link
Show evidence (2 references)
PMID:40555839 SUPPORT Human Clinical
"Houge-Janssens syndrome (HJS) is caused by protein phosphatase type 2A (PP2A) dysfunction."
Overview paper establishing PP2A dysfunction as the unifying cause of HJS.
PMID:39978342 SUPPORT Human Clinical
"a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism."
Establishes dominant-negative mechanism in PPP2R5C (HJS type 4), generalizable to other subtypes.
Disrupted PP2A holoenzyme assembly and function
Pathogenic variants impair the assembly of the PP2A heterotrimer (A-B-C complex) or disrupt substrate binding by the regulatory B subunit. In PPP2R5D, most pathogenic missense variants cluster in conserved regions and impair holoenzyme assembly. In PPP2R5C, variants affect substrate binding, C-subunit binding, or both. Catalytic activity of the phosphatase is variably affected.
Protein dephosphorylation link ↓ DECREASED
Show evidence (2 references)
PMID:39201832 SUPPORT Human Clinical
"Except for E420K and T536R, other missense variants impaired holoenzyme assembly."
In vitro experiments demonstrate that most PPP2R5D missense variants disrupt PP2A holoenzyme assembly.
PMID:39978342 SUPPORT Human Clinical
"All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19)."
Structural analysis showing PPP2R5C variants disrupt substrate or C-subunit binding in the PP2A complex.
Overactivation of growth-promoting kinase pathways
PP2A normally opposes the activity of serine/threonine protein kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased PP2A activity leads to sustained activation of these growth-promoting pathways, converging on mTORC1/p70S6K/RPS6 signaling. Phosphoproteomic analysis of PPP2R5D variant cells shows RPS6 hyperphosphorylation as a shared signaling alteration, with ERK-dependent mTORC1 activation in both E198K and E420K variants, and additional AKT-mediated mTORC1 activation in the E420K variant.
TOR signaling link ↑ INCREASED MAPK cascade link ↑ INCREASED Ras protein signal transduction link ↑ INCREASED
Show evidence (4 references)
PMID:40555839 SUPPORT Human Clinical
"PP2A oppose the activity of serine/threonine protein kinases, including growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic de novo missense variants in several PP2A subunits, some of..."
Directly links PP2A dysfunction to overactivation of both PI3K/AKT/mTOR and RAS/MAPK growth kinase pathways.
PMID:37572851 SUPPORT In Vitro
"We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared signaling alteration, indicative of increased ribosomal protein S6-kinase activity."
Phosphoproteomics of PPP2R5D E198K and E420K cells shows RPS6 hyperphosphorylation as shared convergent signaling alteration.
PMID:37572851 SUPPORT In Vitro
"our data suggests ERK-dependent activation of mTORC1 in both E198K and E420K variant cells, with additional AKT-mediated mTORC1 activation in the E420K variant."
Demonstrates convergence of both ERK/MAPK and AKT pathways on mTORC1 in PPP2R5D variant cells, explaining why multiple growth pathways are co-activated.
+ 1 more reference
Disrupted neuronal development
Patient-derived iPSC neural progenitors are hyper-proliferative, and cortical glutamatergic neurons show increased neurite outgrowth. RNA-seq reveals disruptions in pathways critical for neuronal development, synaptic signaling, and axon guidance. Importantly, these overgrowth phenotypes are not seen in PPP2R5D-null neurons, confirming dominant-negative rather than loss-of-function effects.
Neural progenitor cell link
Nervous system development link ⚠ ABNORMAL
Show evidence (3 references)
PMID:40340253 SUPPORT In Vitro
"Patient-derived neural progenitors were hyper-proliferative, and glutamatergic neurons differentiated from these cells exhibited increased neurite outgrowth."
iPSC study demonstrating neural progenitor hyperproliferation and neuronal overgrowth in PPP2R5D patients.
PMID:40340253 SUPPORT In Vitro
"RNA sequencing (RNA-seq) of glutamatergic neurons derived from patient lines compared to their isogenic controls revealed disruptions in pathways critical for neuronal development, synaptic signaling, and axon guidance."
Transcriptomic evidence of disrupted neurodevelopmental pathways.
PMID:40340253 SUPPORT In Vitro
"neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function."
Key finding confirming dominant-negative rather than haploinsufficiency mechanism.
⬡

Causal Graph

graph LR
    PP2A_subunit_mutations["PP2A subunit mutations"]
    Overactivation_of_growth_promoting_kinase_pathways["Overactivation of growth-promoting kinase pathways"]
    Disrupted_PP2A_holoenzyme_assembly_and_function["Disrupted PP2A holoenzyme assembly and function"]
    Disrupted_neuronal_development["Disrupted neuronal development"]

    PP2A_subunit_mutations --> Disrupted_PP2A_holoenzyme_assembly_and_function
    Disrupted_PP2A_holoenzyme_assembly_and_function --> Overactivation_of_growth_promoting_kinase_pathways
    Overactivation_of_growth_promoting_kinase_pathways --> Disrupted_neuronal_development

    style PP2A_subunit_mutations fill:#dbeafe
    style Overactivation_of_growth_promoting_kinase_pathways fill:#dbeafe
    style Disrupted_PP2A_holoenzyme_assembly_and_function fill:#dbeafe
    style Disrupted_neuronal_development fill:#dbeafe
●

Phenotypes

11
Head and Neck(2) Musculoskeletal(1) Nervous System(8)
Head and Neck 2
Macrocephaly FREQUENT Macrocephaly (HP:0000256)
Show evidence (3 references)
PMID:40555839 SUPPORT Human Clinical
"Decreased PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic de novo missense variants in several PP2A subunits, some of which are associated with macrocephaly if congenital, or cancer if somatic."
Links macrocephaly to decreased PP2A activity and growth-promoting signaling.
PMID:41465181 SUPPORT Human Clinical
"macrocephaly in 25.9% (15/58)"
Quantifies macrocephaly at ~26% in HJS type 2.
PMID:39201832 SUPPORT Human Clinical
"the macrocephaly phenotype was related to negatively charged residues involved in substrate recruitment."
Links macrocephaly to specific structural features of PPP2R5D variants affecting substrate recruitment.
Microcephaly OCCASIONAL Microcephaly (HP:0000252)
Show evidence (1 reference)
PMID:41465181 SUPPORT Human Clinical
"Microcephaly was reported in 17.2% (10/58)"
Quantifies microcephaly at ~17% in HJS type 2.
Musculoskeletal 1
Hypotonia VERY_FREQUENT Hypotonia (HP:0001252)
Show evidence (2 references)
PMID:40555839 SUPPORT Human Clinical
"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."
Prolonged hypotonia listed as a core feature.
PMID:39978342 SUPPORT Human Clinical
"Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features."
Hypotonia confirmed as common in HJS type 4.
Nervous System 8
Global developmental delay VERY_FREQUENT Global developmental delay (HP:0001263)
Show evidence (2 references)
PMID:40555839 SUPPORT Human Clinical
"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."
Overview defines neurodevelopmental delay as a core feature of HJS.
PMID:41465181 SUPPORT Human Clinical
"Developmental delay and intellectual disability were universally present in all patients for whom data were available (100%, 58/58)."
Systematic review of HJS type 2 showing 100% prevalence of DD/ID.
Delayed speech and language development VERY_FREQUENT Delayed speech and language development (HP:0000750)
Show evidence (1 reference)
PMID:40555839 SUPPORT Human Clinical
"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."
Language delay specifically highlighted as a core feature.
Intellectual disability VERY_FREQUENT Intellectual disability (HP:0001249)
Show evidence (2 references)
PMID:41465181 SUPPORT Human Clinical
"Developmental delay and intellectual disability were universally present in all patients for whom data were available (100%, 58/58)."
Universal in HJS type 2 patients.
PMID:39978342 SUPPORT Human Clinical
"The degree of intellectual disability was, on average, milder than in other HJS types."
HJS type 4 shows milder intellectual disability on average.
Seizures FREQUENT Seizure (HP:0001250)
Show evidence (2 references)
PMID:40555839 SUPPORT Human Clinical
"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."
Seizures listed as a core feature with high risk.
PMID:41465181 SUPPORT Human Clinical
"Epilepsy occurred in 50.9% (29/57)"
Quantifies epilepsy prevalence at ~51% in HJS type 2.
Autistic behavior Autistic behavior (HP:0000729)
Show evidence (1 reference)
PMID:40340253 SUPPORT Human Clinical
"Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease."
ASD listed as a characteristic feature of HJS type 1.
Abnormal corpus callosum morphology FREQUENT Abnormal corpus callosum morphology (HP:0001273)
Show evidence (2 references)
PMID:41465181 SUPPORT Human Clinical
"structural brain abnormalities in 83.1% (49/59), with corpus callosum abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most frequent."
Corpus callosum abnormalities in 41% and ventriculomegaly in 32% of HJS type 2 patients.
PMID:40781915 SUPPORT Human Clinical
"The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%)."
Prenatal review showing corpus callosum abnormalities in 50% of prenatally detected HJS type 2 cases.
Ventriculomegaly FREQUENT Ventriculomegaly (HP:0002119)
Show evidence (2 references)
PMID:41465181 SUPPORT Human Clinical
"structural brain abnormalities in 83.1% (49/59), with corpus callosum abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most frequent."
Ventriculomegaly in ~32% of HJS type 2 patients.
PMID:40781915 SUPPORT Human Clinical
"The most common features were ventriculomegaly (92%), agenesis or dysgenesis of the corpus callosum (50%), and congenital heart defects (42%)."
Ventriculomegaly in 92% of prenatally detected HJS type 2 cases.
Parkinsonism Parkinsonism (HP:0001300)
Show evidence (1 reference)
PMID:40340253 SUPPORT Human Clinical
"Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome 1, a rare NDD characterized by macrocephaly, developmental delay, intellectual disability, seizures, autism spectrum disorder, and early-onset Parkinson disease."
Early-onset Parkinson disease listed as characteristic of HJS type 1.
🧬

Genetic Associations

4
PPP2R5D (Causative)
Show evidence (2 references)
PMID:40340253 SUPPORT In Vitro
"neuronal overgrowth phenotypes were not observed in neurons lacking PPP2R5D, suggesting the disorder does not result from loss of function."
Confirms dominant-negative rather than loss-of-function mechanism.
PMID:39201832 SUPPORT Human Clinical
"Thirteen new patients carrying twelve PPP2R5D gene variants were detected, including five novel missense variants and one novel frameshift variant."
Expands the variant spectrum for PPP2R5D.
PPP2R1A (Causative)
Show evidence (1 reference)
PMID:41465181 SUPPORT Human Clinical
"Recurrent hotspots included p.Arg182Trp (n = 12) and p.Arg183Gln (n = 5)."
Identifies recurrent hotspot variants in PPP2R1A.
PPP2CA (Causative)
Show evidence (1 reference)
PMID:40555839 SUPPORT Human Clinical
"dominant pathogenic variants in at least two B subunits (PPP2R5D in HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause Houge-Janssens syndrome."
Overview defining PPP2CA as causative for HJS type 3.
PPP2R5C (Causative)
Show evidence (1 reference)
PMID:39978342 SUPPORT Human Clinical
"PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism."
Key mechanistic insight differentiating dominant-negative from haploinsufficiency.
💊

Treatments

3
Supportive care MAXO:0000950
Management is primarily supportive, focusing on speech therapy, physical therapy, occupational therapy, educational support, and behavioral interventions. No disease-modifying therapy is currently available.
Show evidence (1 reference)
PMID:40555839 SUPPORT Human Clinical
"Hypothetically, small molecules that alleviate substrate blockade by affected B subunits or correct misfolding of affected A subunit, could represent treatment options, but these remain to be found."
Notes that disease-modifying treatments are hypothetical and not yet available, so management remains supportive.
Speech therapy MAXO:0000930
Speech and language therapy to address the prominent language delay.
Show evidence (1 reference)
PMID:40555839 SUPPORT Human Clinical
"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."
Language delay is specifically emphasized, warranting speech therapy.
Genetic counseling MAXO:0000079
Genetic counseling for families. Most variants are de novo with low recurrence risk, though PPP2R5C loss-of-function variants can be inherited.
Show evidence (1 reference)
PMID:41465181 SUPPORT Human Clinical
"Recognition of recurrent hotspot variants and their phenotype associations facilitates diagnosis, prognosis, and genetic counseling."
Review emphasizes the role of genetic counseling based on variant-specific prognostication.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Houge-Janssens Syndrome:

Noonan syndrome MONDO:0018997
Overlapping Features RASopathies including Noonan syndrome share overlapping clinical features with HJS due to convergence on the RAS/MAPK signaling pathway, which PP2A normally opposes. Shared features include developmental delay, macrocephaly, seizures, hypotonia, and dysmorphic facial features.
Distinguishing Features
  • Congenital heart defects (especially pulmonary valve stenosis) are hallmark features of Noonan syndrome but not typical of HJS
  • Short stature is common in Noonan syndrome but not a core feature of HJS
  • Noonan syndrome is caused by variants in RAS/MAPK pathway genes (PTPN11, SOS1, RAF1, KRAS, BRAF) rather than PP2A subunit genes
  • HJS typically presents with more severe language delay relative to overall cognitive level
Show evidence (2 references)
PMID:31250618 SUPPORT Human Clinical
"The frequently seen neurological defects are developmental delay, macrocephaly, seizures, neurocognitive deficits, and structural malformations."
RASopathies share neurodevelopmental features with HJS including DD, macrocephaly, and seizures, because both involve dysregulation of the same downstream kinase pathways.
PMID:40555839 SUPPORT Human Clinical
"PP2A oppose the activity of serine/threonine protein kinases, including growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways."
PP2A directly opposes RAS/MAPK signaling, explaining the phenotypic overlap between HJS and RASopathies.
Megalencephaly-capillary malformation-polymicrogyria syndrome Not Yet Curated MONDO:0011240
Overlapping Features MCAP syndrome, caused by mosaic gain-of-function PIK3CA variants, shares macrocephaly, neurodevelopmental delay, and brain anomalies with HJS. Both conditions involve overactivation of the PI3K/AKT/mTOR pathway. Alpelisib (PI3K inhibitor) is being evaluated for MCAP, highlighting the shared pathway biology.
Distinguishing Features
  • Capillary malformations and cutaneous vascular anomalies are characteristic of MCAP but absent in HJS
  • Polymicrogyria is a hallmark brain finding in MCAP but not typical of HJS
  • MCAP is caused by somatic mosaic PIK3CA variants rather than germline PP2A subunit variants
  • Somatic overgrowth with body asymmetry occurs in MCAP but not HJS
Show evidence (1 reference)
PMID:39806603 SUPPORT Human Clinical
"The megalencephaly capillary malformation polymicrogyria (MCAP syndrome) results from mosaic gain-of-function PIK3CA variants. The main clinical features are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies."
MCAP shares macrocephaly and NDD with HJS through the shared PI3K/AKT/mTOR pathway that PP2A opposes.
PTEN hamartoma tumor syndrome Not Yet Curated MONDO:0017623
Overlapping Features PTEN loss-of-function leads to overactivation of the PI3K/AKT/mTOR pathway, the same pathway that PP2A normally opposes. PTEN hamartoma tumor syndrome (including Cowden and Bannayan-Riley-Ruvalcaba syndromes) shares macrocephaly and autism spectrum features with HJS.
Distinguishing Features
  • Hamartomatous growths (trichilemmomas, intestinal polyps) are characteristic of PTEN syndromes but absent in HJS
  • Increased cancer risk (breast, thyroid, endometrial) is a major feature of PTEN syndromes but not of HJS
  • Macrocephaly in PTEN syndromes is typically more pronounced
  • PTEN mutations are loss-of-function whereas HJS variants act through dominant-negative mechanisms on PP2A
Show evidence (1 reference)
PMID:34625286 SUPPORT Human Clinical
"we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as a common underlying mechanism"
PTEN acts on the same PI3K-mTOR pathway that PP2A opposes, explaining shared macrocephaly and neurodevelopmental features.
Smith-Kingsmore syndrome Not Yet Curated MONDO:0014716
Overlapping Features Smith-Kingsmore syndrome is caused by heterozygous gain-of-function MTOR variants, directly activating the mTOR kinase that PP2A normally opposes. The clinical overlap with HJS includes macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures.
Distinguishing Features
  • Caused by direct gain-of-function MTOR variants rather than PP2A subunit mutations
  • mTOR inhibitors (rapamycin) are being explored as treatment for SKS but not for HJS
  • Circadian rhythm and sleep-wake disturbances are prominent in SKS
  • Small thorax may be present in SKS but is not seen in HJS
Show evidence (1 reference)
PMID:39030910 SUPPORT Human Clinical
"Heterozygous de novo or inherited gain-of-function mutations in the MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant condition, and individuals with SKS display macrocephaly/megalencephaly, developmental delay, intellectual disability, and seizures."
SKS shares macrocephaly, DD, ID, and seizures with HJS through the shared mTOR pathway that PP2A opposes.
Angelman syndrome Not Yet Curated MONDO:0007113
Overlapping Features Angelman syndrome shares severe speech delay, seizures, and behavioral features with HJS, potentially leading to diagnostic confusion before molecular testing. Both conditions present with intellectual disability and movement abnormalities.
Distinguishing Features
  • Severe absence of speech is characteristic of Angelman syndrome, whereas HJS shows delayed but not absent language
  • Happy demeanor with frequent laughter is a hallmark of Angelman syndrome
  • Caused by loss of maternal UBE3A expression on chromosome 15, not PP2A subunit mutations
  • Microcephaly is common in Angelman syndrome, whereas HJS more often shows macrocephaly
  • Characteristic EEG pattern in Angelman syndrome
Show evidence (1 reference)
PMID:40555839 SUPPORT Human Clinical
"The core features are neurodevelopmental delay, especially concerning language, prolonged hypotonia, high risk of seizures, and behavior problems."
The combination of prominent language delay, seizures, hypotonia, and behavioral problems in HJS overlaps with Angelman syndrome presentation.
{ }

Source YAML

click to show 
name: Houge-Janssens Syndrome
creation_date: "2026-02-15T00:00:00Z"
updated_date: "2026-02-17T21:53:14Z"
category: Mendelian
description: >
  Houge-Janssens syndrome (HJS) is a group of neurodevelopmental disorders caused
  by dysfunction of protein phosphatase type 2A (PP2A). PP2A is a heterotrimeric
  serine/threonine phosphatase composed of a catalytic (C), scaffolding (A), and
  regulatory (B) subunit. PP2A opposes the activity of growth-promoting kinases of
  the
  PIK3CA/AKT/mTOR and RAS/MAPK pathways. Core clinical features include neurodevelopmental
  delay (especially affecting language), prolonged hypotonia, high risk of seizures,
  behavioral problems, and variable head circumference abnormalities. Four subtypes
  are
  recognized based on the affected PP2A subunit gene: HJS type 1 (PPP2R5D), HJS type
  2
  (PPP2R1A), HJS type 3 (PPP2CA), and HJS type 4 (PPP2R5C). Most pathogenic variants
  are de novo heterozygous missense changes acting through dominant-negative mechanisms.
disease_term:
  preferred_term: Houge-Janssens syndrome
  term:
    id: MONDO:0957553
    label: Houge-Janssens syndrome
parents:
- Neurodevelopmental disorder
- PP2A-related disorder
synonyms:
- HJS
- PP2A-related neurodevelopmental disorder
- Jordan's Syndrome
- PPP2R5D-related neurodevelopmental disorder
prevalence:
- population: Global
  notes: >
    Houge-Janssens syndrome is rare. No formal prevalence estimates exist.
    The largest reported cohorts include 60 PPP2R1A patients (HJS type 2)
    and 26 PPP2R5C patients (HJS type 4). HJS type 1 (PPP2R5D) is the
    most commonly reported subtype, with multiple case series totaling
    over 50 patients.
  evidence:
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 16 studies representing 60 patients with PPP2R1A-related
      disorders."
    explanation: Systematic review identified 60 PPP2R1A patients across 16
      studies, indicating rarity.
  - reference: PMID:39978342
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe an additional condition in the HJS spectrum in 26 individuals
      with variants in PPP2R5C"
    explanation: 26 individuals reported for the HJS type 4 subtype.
has_subtypes:
- name: Houge-Janssens syndrome type 1 (PPP2R5D)
  description: >
    Most well-characterized subtype, caused by de novo missense variants in PPP2R5D
    encoding the B56delta regulatory subunit. Features include macrocephaly,
    developmental delay, intellectual disability, seizures, ASD, and early-onset
    parkinsonism. Recurrent variants include E198K and E420K.
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant pathogenic variants in at least two B subunits (PPP2R5D in
      HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A
      in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause
      Houge-Janssens syndrome."
    explanation: Overview paper defining HJS type 1 as PPP2R5D-related.
  - reference: PMID:39201832
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NDDs related to the PPP2R5D gene have recently been defined as Houge-Janssens
      syndrome 1."
    explanation: Confirms PPP2R5D as the gene causing HJS type 1.
- name: Houge-Janssens syndrome type 2 (PPP2R1A)
  subtype_term:
    preferred_term: Houge-Janssens syndrome 2
    term:
      id: MONDO:0014605
      label: Houge-Janssens syndrome 2
  description: >
    Caused by de novo missense variants in PPP2R1A encoding the Aalpha scaffolding
    subunit.
    Recurrent hotspots include p.Arg182Trp and p.Arg183Gln in HEAT repeats 5-7.
    Developmental delay and intellectual disability are universal. Epilepsy occurs
    in ~51%
    and structural brain abnormalities in ~83%, with corpus callosum abnormalities
    and
    ventriculomegaly most frequent.
  evidence:
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified 16 studies representing 60 patients with PPP2R1A-related
      disorders. Twenty-six distinct pathogenic variants were identified; these were
      predominantly de novo heterozygous missense changes clustering within HEAT repeats
      5-7."
    explanation: Systematic review of 60 PPP2R1A patients defining the clinical
      spectrum of HJS type 2.
  - reference: PMID:40781915
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Houge-Janssens syndrome type 2 (HJS2, OMIM 616362) is a rare neurodevelopmental
      disorder caused by pathogenic variants in PPP2R1A, typically characterized postnatally
      by hypotonia, developmental delay, intellectual disability, and distinctive
      craniofacial features."
    explanation: Case report confirming HJS2 phenotype including prenatal
      features.
- name: Houge-Janssens syndrome type 3 (PPP2CA)
  subtype_term:
    preferred_term: Houge-Janssens syndrome 3
    term:
      id: MONDO:0032697
      label: Houge-Janssens syndrome 3
  description: >
    Caused by de novo missense and loss-of-function variants in PPP2CA encoding the
    Calpha catalytic subunit.
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant pathogenic variants in at least two B subunits (PPP2R5D in
      HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A
      in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause
      Houge-Janssens syndrome."
    explanation: Overview defines HJS type 3 as PPP2CA-related.
- name: Houge-Janssens syndrome type 4 (PPP2R5C)
  subtype_term:
    preferred_term: Houge-Janssens syndrome 4
    term:
      id: MONDO:0978293
      label: Houge-Janssens syndrome 4
  description: >
    Caused by de novo missense variants in PPP2R5C encoding the B56gamma regulatory
    subunit. Clinical features are within the HJS spectrum with strongest resemblance
    to HJS type 1. Average intellectual disability is milder than other subtypes.
    Head circumferences are above average or macrocephalic. Pathogenic mechanism is
    dominant-negative on substrate dephosphorylation.
  evidence:
  - reference: PMID:39978342
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical features were well within the HJS spectrum with strongest
      resemblance to HJS type 1, caused by B56delta variants. Common features were
      neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral
      problems, and mildly dysmorphic facial features."
    explanation: Defines HJS type 4 clinical spectrum in 26 individuals with
      PPP2R5C variants.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  description: >
    Houge-Janssens syndrome follows autosomal dominant inheritance. Nearly all
    pathogenic variants arise de novo as heterozygous missense changes.
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent pathogenic de novo missense variants in several PP2A subunits,
      some of which are associated with macrocephaly if congenital, or cancer if somatic."
    explanation: Overview confirms de novo dominant variants across PP2A
      subunits.
pathophysiology:
- name: PP2A subunit mutations
  description: >
    De novo dominant missense variants in PP2A subunit genes (PPP2R5D, PPP2R1A,
    PPP2CA, PPP2R5C) disrupt the structure or function of the affected subunit.
    In PPP2R5D, variants such as E198K and E420K cause dominant-negative effects
    rather than loss of function.
  genes:
  - preferred_term: PPP2R5D
    term:
      id: hgnc:9312
      label: PPP2R5D
  - preferred_term: PPP2R1A
    term:
      id: hgnc:9302
      label: PPP2R1A
  - preferred_term: PPP2CA
    term:
      id: hgnc:9299
      label: PPP2CA
  - preferred_term: PPP2R5C
    term:
      id: hgnc:9311
      label: PPP2R5C
  downstream:
  - target: Disrupted PP2A holoenzyme assembly and function
    description: Mutant subunits impair holoenzyme assembly or catalytic
      activity through dominant-negative mechanisms.
    evidence:
    - reference: PMID:39201832
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Except for E420K and T536R, other missense variants impaired holoenzyme
        assembly."
      explanation: Demonstrates that PP2A subunit mutations lead to disrupted
        holoenzyme assembly.
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Houge-Janssens syndrome (HJS) is caused by protein phosphatase type
      2A (PP2A) dysfunction."
    explanation: Overview paper establishing PP2A dysfunction as the unifying
      cause of HJS.
  - reference: PMID:39978342
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a dominant-negative mechanism on substrate dephosphorylation or general
      PP2A function is the most likely pathogenic mechanism."
    explanation: Establishes dominant-negative mechanism in PPP2R5C (HJS type
      4), generalizable to other subtypes.
- name: Disrupted PP2A holoenzyme assembly and function
  description: >
    Pathogenic variants impair the assembly of the PP2A heterotrimer (A-B-C complex)
    or disrupt substrate binding by the regulatory B subunit. In PPP2R5D, most
    pathogenic missense variants cluster in conserved regions and impair holoenzyme
    assembly. In PPP2R5C, variants affect substrate binding, C-subunit binding, or
    both. Catalytic activity of the phosphatase is variably affected.
  notes: >
    The affected molecular function is protein serine/threonine phosphatase activity
    (GO:0004722). PP2A is the major serine/threonine phosphatase opposing growth
    kinase signaling.
  biological_processes:
  - preferred_term: Protein dephosphorylation
    modifier: DECREASED
    term:
      id: GO:0006470
      label: protein dephosphorylation
  downstream:
  - target: Overactivation of growth-promoting kinase pathways
    description: Reduced PP2A dephosphorylation activity leads to sustained
      kinase signaling.
    evidence:
    - reference: PMID:40555839
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "PP2A oppose the activity of serine/threonine protein kinases, including
        growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased
        PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic
        de novo missense variants in several PP2A subunits, some of which are associated
        with macrocephaly if congenital, or cancer if somatic."
      explanation: Links disrupted PP2A function to overactivation of growth
        kinase pathways.
  evidence:
  - reference: PMID:39201832
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Except for E420K and T536R, other missense variants impaired holoenzyme
      assembly."
    explanation: In vitro experiments demonstrate that most PPP2R5D missense
      variants disrupt PP2A holoenzyme assembly.
  - reference: PMID:39978342
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All variants affected either substrate binding (2/19), C-subunit binding
      (2/19), or both (15/19)."
    explanation: Structural analysis showing PPP2R5C variants disrupt substrate
      or C-subunit binding in the PP2A complex.
- name: Overactivation of growth-promoting kinase pathways
  description: >
    PP2A normally opposes the activity of serine/threonine protein kinases of the
    PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased PP2A activity leads to
    sustained activation of these growth-promoting pathways, converging on
    mTORC1/p70S6K/RPS6 signaling. Phosphoproteomic analysis of PPP2R5D variant
    cells shows RPS6 hyperphosphorylation as a shared signaling alteration, with
    ERK-dependent mTORC1 activation in both E198K and E420K variants, and
    additional AKT-mediated mTORC1 activation in the E420K variant.
  biological_processes:
  - preferred_term: TOR signaling
    modifier: INCREASED
    term:
      id: GO:0031929
      label: TOR signaling
  - preferred_term: MAPK cascade
    modifier: INCREASED
    term:
      id: GO:0000165
      label: MAPK cascade
  - preferred_term: Ras protein signal transduction
    modifier: INCREASED
    term:
      id: GO:0007265
      label: Ras protein signal transduction
  downstream:
  - target: Disrupted neuronal development
    description: Overactive growth signaling impairs normal neural progenitor
      proliferation and differentiation.
    evidence:
    - reference: PMID:40340253
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Patient-derived neural progenitors were hyper-proliferative, and glutamatergic
        neurons differentiated from these cells exhibited increased neurite outgrowth."
      explanation: Demonstrates that overactive growth signaling from PP2A
        dysfunction leads to neuronal overgrowth.
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PP2A oppose the activity of serine/threonine protein kinases, including
      growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways. Decreased
      PP2A activity can thus be growth promoting, as evidenced by recurrent pathogenic
      de novo missense variants in several PP2A subunits, some of which are associated
      with macrocephaly if congenital, or cancer if somatic."
    explanation: Directly links PP2A dysfunction to overactivation of both
      PI3K/AKT/mTOR and RAS/MAPK growth kinase pathways.
  - reference: PMID:37572851
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We observed ribosomal protein S6 (RPS6) hyperphosphorylation as a shared
      signaling alteration, indicative of increased ribosomal protein S6-kinase activity."
    explanation: Phosphoproteomics of PPP2R5D E198K and E420K cells shows RPS6
      hyperphosphorylation as shared convergent signaling alteration.
  - reference: PMID:37572851
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "our data suggests ERK-dependent activation of mTORC1 in both E198K and
      E420K variant cells, with additional AKT-mediated mTORC1 activation in the E420K
      variant."
    explanation: Demonstrates convergence of both ERK/MAPK and AKT pathways on
      mTORC1 in PPP2R5D variant cells, explaining why multiple growth pathways
      are co-activated.
  - reference: PMID:39728742
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There is evidence that the PP2A-PPP2R5D complex is involved in regulating
      the phosphatidylinositol 3-kinase (PI3K)/AKT signalling pathway, which is crucial
      for several cellular processes, including the pathogenesis and progression of
      haemangiomas."
    explanation: Documents PP2A-PPP2R5D regulation of PI3K/AKT signaling.
- name: Disrupted neuronal development
  description: >
    Patient-derived iPSC neural progenitors are hyper-proliferative, and cortical
    glutamatergic neurons show increased neurite outgrowth. RNA-seq reveals
    disruptions in pathways critical for neuronal development, synaptic signaling,
    and axon guidance. Importantly, these overgrowth phenotypes are not seen in
    PPP2R5D-null neurons, confirming dominant-negative rather than loss-of-function
    effects.
  cell_types:
  - preferred_term: Neural progenitor cell
    term:
      id: CL:0011020
      label: neural progenitor cell
  biological_processes:
  - preferred_term: Nervous system development
    modifier: ABNORMAL
    term:
      id: GO:0007399
      label: nervous system development
  evidence:
  - reference: PMID:40340253
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient-derived neural progenitors were hyper-proliferative, and glutamatergic
      neurons differentiated from these cells exhibited increased neurite outgrowth."
    explanation: iPSC study demonstrating neural progenitor hyperproliferation
      and neuronal overgrowth in PPP2R5D patients.
  - reference: PMID:40340253
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "RNA sequencing (RNA-seq) of glutamatergic neurons derived from patient
      lines compared to their isogenic controls revealed disruptions in pathways critical
      for neuronal development, synaptic signaling, and axon guidance."
    explanation: Transcriptomic evidence of disrupted neurodevelopmental
      pathways.
  - reference: PMID:40340253
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "neuronal overgrowth phenotypes were not observed in neurons lacking
      PPP2R5D, suggesting the disorder does not result from loss of function."
    explanation: Key finding confirming dominant-negative rather than
      haploinsufficiency mechanism.
phenotypes:
- name: Global developmental delay
  description: >
    Universal feature across all HJS subtypes. Neurodevelopmental delay with
    particular impact on language acquisition.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Overview defines neurodevelopmental delay as a core feature of
      HJS.
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay and intellectual disability were universally present
      in all patients for whom data were available (100%, 58/58)."
    explanation: Systematic review of HJS type 2 showing 100% prevalence of
      DD/ID.
- name: Delayed speech and language development
  description: >
    Language delay is particularly prominent across HJS subtypes and is emphasized
    as a core feature.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Language delay specifically highlighted as a core feature.
- name: Intellectual disability
  description: >
    Variable severity across subtypes, from mild (HJS type 4) to severe.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Developmental delay and intellectual disability were universally present
      in all patients for whom data were available (100%, 58/58)."
    explanation: Universal in HJS type 2 patients.
  - reference: PMID:39978342
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The degree of intellectual disability was, on average, milder than in
      other HJS types."
    explanation: HJS type 4 shows milder intellectual disability on average.
- name: Hypotonia
  description: >
    Prolonged muscular hypotonia is a core feature across all HJS subtypes.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Prolonged hypotonia listed as a core feature.
  - reference: PMID:39978342
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Common features were neurodevelopmental delay and hypotonia, with a
      high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features."
    explanation: Hypotonia confirmed as common in HJS type 4.
- name: Seizures
  description: >
    High risk of seizures is a core feature of HJS. Epilepsy occurs in approximately
    51% of HJS type 2 patients and is common across all subtypes.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Seizures listed as a core feature with high risk.
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Epilepsy occurred in 50.9% (29/57)"
    explanation: Quantifies epilepsy prevalence at ~51% in HJS type 2.
- name: Macrocephaly
  description: >
    Head circumference above normal is common, particularly in HJS type 1 (PPP2R5D)
    and type 4 (PPP2R5C). In HJS type 2, macrocephaly occurs in about 26% of patients.
    Related to overactivation of growth-promoting kinase pathways.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Decreased PP2A activity can thus be growth promoting, as evidenced by
      recurrent pathogenic de novo missense variants in several PP2A subunits, some
      of which are associated with macrocephaly if congenital, or cancer if somatic."
    explanation: Links macrocephaly to decreased PP2A activity and
      growth-promoting signaling.
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "macrocephaly in 25.9% (15/58)"
    explanation: Quantifies macrocephaly at ~26% in HJS type 2.
  - reference: PMID:39201832
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the macrocephaly phenotype was related to negatively charged residues
      involved in substrate recruitment."
    explanation: Links macrocephaly to specific structural features of PPP2R5D
      variants affecting substrate recruitment.
- name: Microcephaly
  description: >
    Microcephaly can also occur in a subset of HJS patients, particularly HJS type
    2,
    reported in approximately 17% of PPP2R1A patients.
  frequency: OCCASIONAL
  subtype: Houge-Janssens syndrome type 2 (PPP2R1A)
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microcephaly was reported in 17.2% (10/58)"
    explanation: Quantifies microcephaly at ~17% in HJS type 2.
- name: Autistic behavior
  description: >
    Behavioral problems including autism spectrum disorder features are common.
  phenotype_term:
    preferred_term: Autistic behavior
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:40340253
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome
      1, a rare NDD characterized by macrocephaly, developmental delay, intellectual
      disability, seizures, autism spectrum disorder, and early-onset Parkinson disease."
    explanation: ASD listed as a characteristic feature of HJS type 1.
- name: Abnormal corpus callosum morphology
  description: >
    Corpus callosum abnormalities including agenesis, dysgenesis, or hypoplasia
    are a common structural brain finding, particularly in HJS type 2 (~41%).
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Abnormal corpus callosum morphology
    term:
      id: HP:0001273
      label: Abnormal corpus callosum morphology
  evidence:
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural brain abnormalities in 83.1% (49/59), with corpus callosum
      abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most
      frequent."
    explanation: Corpus callosum abnormalities in 41% and ventriculomegaly in
      32% of HJS type 2 patients.
  - reference: PMID:40781915
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common features were ventriculomegaly (92%), agenesis or dysgenesis
      of the corpus callosum (50%), and congenital heart defects (42%)."
    explanation: Prenatal review showing corpus callosum abnormalities in 50% of
      prenatally detected HJS type 2 cases.
- name: Ventriculomegaly
  description: >
    Enlarged cerebral ventricles are a common structural brain finding.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "structural brain abnormalities in 83.1% (49/59), with corpus callosum
      abnormalities (40.7%, 24/59) and ventriculomegaly (32.2%, 19/59) being most
      frequent."
    explanation: Ventriculomegaly in ~32% of HJS type 2 patients.
  - reference: PMID:40781915
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common features were ventriculomegaly (92%), agenesis or dysgenesis
      of the corpus callosum (50%), and congenital heart defects (42%)."
    explanation: Ventriculomegaly in 92% of prenatally detected HJS type 2
      cases.
- name: Parkinsonism
  description: >
    Early-onset parkinsonism has been reported as a feature of HJS type 1 (PPP2R5D).
  subtype: Houge-Janssens syndrome type 1 (PPP2R5D)
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:40340253
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous missense variants in PPP2R5D cause Houge-Janssens syndrome
      1, a rare NDD characterized by macrocephaly, developmental delay, intellectual
      disability, seizures, autism spectrum disorder, and early-onset Parkinson disease."
    explanation: Early-onset Parkinson disease listed as characteristic of HJS
      type 1.
genetic:
- name: PPP2R5D
  gene_term:
    preferred_term: PPP2R5D
    term:
      id: hgnc:9312
      label: PPP2R5D
  association: Causative
  notes: >
    Encodes the B56delta regulatory subunit of PP2A. De novo heterozygous missense
    variants cause HJS type 1. Most pathogenic variants cluster in three conserved
    regions. Dominant-negative mechanism, not loss of function.
  evidence:
  - reference: PMID:40340253
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "neuronal overgrowth phenotypes were not observed in neurons lacking
      PPP2R5D, suggesting the disorder does not result from loss of function."
    explanation: Confirms dominant-negative rather than loss-of-function
      mechanism.
  - reference: PMID:39201832
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thirteen new patients carrying twelve PPP2R5D gene variants were detected,
      including five novel missense variants and one novel frameshift variant."
    explanation: Expands the variant spectrum for PPP2R5D.
  variants:
  - name: E198K
    description: >
      Most common disease-causing missense variant in PPP2R5D. Allele-specific
      antisense oligonucleotides targeting this variant can reverse neuronal
      overgrowth phenotypes in patient-derived neurons.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:40340253
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "antisense oligonucleotides (ASOs) were designed to selectively knock
        down the E198K allele, the most common disease-causing missense variant. The
        most effective ASOs reversed neurite outgrowth defects in patient-derived
        neurons."
      explanation: Demonstrates therapeutic potential of allele-specific
        knockdown for the E198K variant.
- name: PPP2R1A
  gene_term:
    preferred_term: PPP2R1A
    term:
      id: hgnc:9302
      label: PPP2R1A
  association: Causative
  notes: >
    Encodes the Aalpha scaffolding subunit of PP2A. De novo heterozygous missense
    variants cause HJS type 2. Recurrent hotspots include p.Arg182Trp and p.Arg183Gln
    in HEAT repeats 5-7.
  evidence:
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent hotspots included p.Arg182Trp (n = 12) and p.Arg183Gln (n
      = 5)."
    explanation: Identifies recurrent hotspot variants in PPP2R1A.
- name: PPP2CA
  gene_term:
    preferred_term: PPP2CA
    term:
      id: hgnc:9299
      label: PPP2CA
  association: Causative
  notes: >
    Encodes the Calpha catalytic subunit of PP2A. De novo missense and
    loss-of-function variants cause HJS type 3.
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant pathogenic variants in at least two B subunits (PPP2R5D in
      HJS type 1 and PPP2R5C in HJS type 4), the major scaffolding subunit (PPP2R1A
      in HJS type 2) and the major catalytic subunit (PPP2CA in HJS type 3) can cause
      Houge-Janssens syndrome."
    explanation: Overview defining PPP2CA as causative for HJS type 3.
- name: PPP2R5C
  gene_term:
    preferred_term: PPP2R5C
    term:
      id: hgnc:9311
      label: PPP2R5C
  association: Causative
  notes: >
    Encodes the B56gamma regulatory subunit of PP2A. De novo missense variants
    cause HJS type 4. Total loss-of-function variants can be inherited from
    non-symptomatic parents, implying a dominant-negative mechanism.
  evidence:
  - reference: PMID:39978342
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic
      parent. This implies that a dominant-negative mechanism on substrate dephosphorylation
      or general PP2A function is the most likely pathogenic mechanism."
    explanation: Key mechanistic insight differentiating dominant-negative from
      haploinsufficiency.
treatments:
- name: Supportive care
  description: >
    Management is primarily supportive, focusing on speech therapy, physical therapy,
    occupational therapy, educational support, and behavioral interventions. No
    disease-modifying therapy is currently available.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypothetically, small molecules that alleviate substrate blockade by
      affected B subunits or correct misfolding of affected A subunit, could represent
      treatment options, but these remain to be found."
    explanation: Notes that disease-modifying treatments are hypothetical and
      not yet available, so management remains supportive.
- name: Speech therapy
  description: >
    Speech and language therapy to address the prominent language delay.
  treatment_term:
    preferred_term: speech therapy
    term:
      id: MAXO:0000930
      label: speech therapy
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: Language delay is specifically emphasized, warranting speech
      therapy.
- name: Genetic counseling
  description: >
    Genetic counseling for families. Most variants are de novo with low recurrence
    risk, though PPP2R5C loss-of-function variants can be inherited.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:41465181
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recognition of recurrent hotspot variants and their phenotype associations
      facilitates diagnosis, prognosis, and genetic counseling."
    explanation: Review emphasizes the role of genetic counseling based on
      variant-specific prognostication.
differential_diagnoses:
- name: Noonan syndrome
  disease_term:
    preferred_term: Noonan syndrome
    term:
      id: MONDO:0018997
      label: Noonan syndrome
  description: >
    RASopathies including Noonan syndrome share overlapping clinical features with
    HJS due to convergence on the RAS/MAPK signaling pathway, which PP2A normally
    opposes. Shared features include developmental delay, macrocephaly, seizures,
    hypotonia, and dysmorphic facial features.
  distinguishing_features:
  - Congenital heart defects (especially pulmonary valve stenosis) are hallmark
    features of Noonan syndrome but not typical of HJS
  - Short stature is common in Noonan syndrome but not a core feature of HJS
  - Noonan syndrome is caused by variants in RAS/MAPK pathway genes (PTPN11,
    SOS1, RAF1, KRAS, BRAF) rather than PP2A subunit genes
  - HJS typically presents with more severe language delay relative to overall
    cognitive level
  evidence:
  - reference: PMID:31250618
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequently seen neurological defects are developmental delay, macrocephaly,
      seizures, neurocognitive deficits, and structural malformations."
    explanation: RASopathies share neurodevelopmental features with HJS
      including DD, macrocephaly, and seizures, because both involve
      dysregulation of the same downstream kinase pathways.
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PP2A oppose the activity of serine/threonine protein kinases, including
      growth promoting kinases of the PIK3CA/AKT/mTOR and RAS/MAPK pathways."
    explanation: PP2A directly opposes RAS/MAPK signaling, explaining the
      phenotypic overlap between HJS and RASopathies.
- name: Megalencephaly-capillary malformation-polymicrogyria syndrome
  disease_term:
    preferred_term: megalencephaly-capillary malformation-polymicrogyria
      syndrome
    term:
      id: MONDO:0011240
      label: megalencephaly-capillary malformation-polymicrogyria syndrome
  description: >
    MCAP syndrome, caused by mosaic gain-of-function PIK3CA variants, shares macrocephaly,
    neurodevelopmental delay, and brain anomalies with HJS. Both conditions involve
    overactivation of the PI3K/AKT/mTOR pathway. Alpelisib (PI3K inhibitor) is being
    evaluated for MCAP, highlighting the shared pathway biology.
  distinguishing_features:
  - Capillary malformations and cutaneous vascular anomalies are characteristic
    of MCAP but absent in HJS
  - Polymicrogyria is a hallmark brain finding in MCAP but not typical of HJS
  - MCAP is caused by somatic mosaic PIK3CA variants rather than germline PP2A
    subunit variants
  - Somatic overgrowth with body asymmetry occurs in MCAP but not HJS
  evidence:
  - reference: PMID:39806603
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The megalencephaly capillary malformation polymicrogyria (MCAP syndrome)
      results from mosaic gain-of-function PIK3CA variants. The main clinical features
      are macrocephaly, somatic overgrowth, neurodevelopmental delay and brain anomalies."
    explanation: MCAP shares macrocephaly and NDD with HJS through the shared
      PI3K/AKT/mTOR pathway that PP2A opposes.
- name: PTEN hamartoma tumor syndrome
  disease_term:
    preferred_term: PTEN hamartoma tumor syndrome
    term:
      id: MONDO:0017623
      label: PTEN hamartoma tumor syndrome
  description: >
    PTEN loss-of-function leads to overactivation of the PI3K/AKT/mTOR pathway, the
    same pathway that PP2A normally opposes. PTEN hamartoma tumor syndrome (including
    Cowden and Bannayan-Riley-Ruvalcaba syndromes) shares macrocephaly and autism
    spectrum features with HJS.
  distinguishing_features:
  - Hamartomatous growths (trichilemmomas, intestinal polyps) are characteristic
    of PTEN syndromes but absent in HJS
  - Increased cancer risk (breast, thyroid, endometrial) is a major feature of
    PTEN syndromes but not of HJS
  - Macrocephaly in PTEN syndromes is typically more pronounced
  - PTEN mutations are loss-of-function whereas HJS variants act through
    dominant-negative mechanisms on PP2A
  evidence:
  - reference: PMID:34625286
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we review and discuss phenotypic, genomic, and molecular similarities
      between ASD and CH, and identify the PTEN-PI3K-mTOR (phosphatase and tensin
      homolog-phosphoinositide 3-kinase-mammalian target of rapamycin) pathway as
      a common underlying mechanism"
    explanation: PTEN acts on the same PI3K-mTOR pathway that PP2A opposes,
      explaining shared macrocephaly and neurodevelopmental features.
- name: Smith-Kingsmore syndrome
  disease_term:
    preferred_term: macrocephaly-intellectual disability-neurodevelopmental
      disorder-small thorax syndrome
    term:
      id: MONDO:0014716
      label: macrocephaly-intellectual disability-neurodevelopmental
        disorder-small thorax syndrome
  description: >
    Smith-Kingsmore syndrome is caused by heterozygous gain-of-function MTOR variants,
    directly activating the mTOR kinase that PP2A normally opposes. The clinical
    overlap with HJS includes macrocephaly/megalencephaly, developmental delay,
    intellectual disability, and seizures.
  distinguishing_features:
  - Caused by direct gain-of-function MTOR variants rather than PP2A subunit
    mutations
  - mTOR inhibitors (rapamycin) are being explored as treatment for SKS but not
    for HJS
  - Circadian rhythm and sleep-wake disturbances are prominent in SKS
  - Small thorax may be present in SKS but is not seen in HJS
  evidence:
  - reference: PMID:39030910
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous de novo or inherited gain-of-function mutations in the
      MTOR gene cause Smith-Kingsmore syndrome (SKS). SKS is a rare autosomal dominant
      condition, and individuals with SKS display macrocephaly/megalencephaly, developmental
      delay, intellectual disability, and seizures."
    explanation: SKS shares macrocephaly, DD, ID, and seizures with HJS through
      the shared mTOR pathway that PP2A opposes.
- name: Angelman syndrome
  disease_term:
    preferred_term: Angelman syndrome
    term:
      id: MONDO:0007113
      label: Angelman syndrome
  description: >
    Angelman syndrome shares severe speech delay, seizures, and behavioral features
    with HJS, potentially leading to diagnostic confusion before molecular testing.
    Both conditions present with intellectual disability and movement abnormalities.
  distinguishing_features:
  - Severe absence of speech is characteristic of Angelman syndrome, whereas HJS
    shows delayed but not absent language
  - Happy demeanor with frequent laughter is a hallmark of Angelman syndrome
  - Caused by loss of maternal UBE3A expression on chromosome 15, not PP2A
    subunit mutations
  - Microcephaly is common in Angelman syndrome, whereas HJS more often shows
    macrocephaly
  - Characteristic EEG pattern in Angelman syndrome
  evidence:
  - reference: PMID:40555839
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The core features are neurodevelopmental delay, especially concerning
      language, prolonged hypotonia, high risk of seizures, and behavior problems."
    explanation: The combination of prominent language delay, seizures,
      hypotonia, and behavioral problems in HJS overlaps with Angelman syndrome
      presentation.
notes: >
  Houge-Janssens syndrome represents a PP2A-opathy with potential for targeted
  therapies. Allele-specific antisense oligonucleotides targeting PPP2R5D E198K
  have shown reversal of neuronal overgrowth phenotypes in iPSC-derived neurons
  (PMID:40340253). Hypothetical small-molecule approaches to alleviate substrate
  blockade or correct subunit misfolding have been proposed but not yet realized.
  Some PP2A variants are somatically recurrent in cancer, highlighting the dual
  role of PP2A as both a developmental and tumor-suppressive regulator.
classifications:
  harrisons_chapter:
  - classification_value: nervous system disorder
    evidence:
    - reference: PMID:40555839
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The core features are neurodevelopmental delay, especially concerning
        language, prolonged hypotonia, high risk of seizures, and behavior problems."
      explanation: Core features are neurological, placing HJS under nervous
        system disorders.
  - classification_value: hereditary disease
    evidence:
    - reference: PMID:40555839
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "recurrent pathogenic de novo missense variants in several PP2A subunits,
        some of which are associated with macrocephaly if congenital, or cancer if
        somatic."
      explanation: HJS is caused by germline de novo genetic variants,
        classifying it as a hereditary disease.
  mechanistic_category:
  - classification_value: RASopathy
    notes: >
      HJS is not a classical RASopathy but is mechanistically related as a
      PP2A-opathy. PP2A directly opposes the RAS/MAPK and PI3K/AKT/mTOR
      kinase pathways, so loss of PP2A function converges on the same
      downstream signaling as RASopathies. No dedicated PP2A-opathy category
      exists in the current mechanistic nosology.
    evidence:
    - reference: PMID:37572851
      supports: PARTIAL
      evidence_source: IN_VITRO
      snippet: "our data suggests ERK-dependent activation of mTORC1 in both E198K
        and E420K variant cells, with additional AKT-mediated mTORC1 activation in
        the E420K variant."
      explanation: ERK/MAPK pathway activation in PPP2R5D variant cells supports
        classification as RASopathy-adjacent, though the primary defect is in
        PP2A rather than a RAS/MAPK pathway component.
datasets:
references:
- reference: DOI:10.1016/j.jbc.2023.105203
  title: Transcription factor UBF depletion in mouse cells results in
    downregulation of both downstream and upstream elements of the rRNA
    transcription network
  findings: []
- reference: DOI:10.1093/hmg/ddy049
  title: A recurrent de novo missense mutation in UBTF causes developmental
    neuroregression
  findings: []
- reference: DOI:10.1101/2022.11.02.514882
  title: Early maturation and hyperexcitability is a shared phenotype of
    cortical neurons derived from different ASD-associated mutations
  findings: []
- reference: DOI:10.1212/nxg.0000000000200098
  title: Expanding the Clinical Spectrum of <i>UBTF</i> -Related
    Neurodevelopmental Disorder
  findings: []
- reference: DOI:10.3389/fgene.2023.1225832
  title: HMG-boxes, ribosomopathies and neurodegenerative disease
  findings: []
- reference: DOI:10.3390/biomedicines12051092
  title: Polymerase I as a Target for Treating Neurodegenerative Disorders
  findings: []
- reference: DOI:10.3390/brainsci14020179
  title: An Overview of UBTF Neuroregression Syndrome
  findings: []