Noonan Syndrome-like Disorder with Loose Anagen Hair

Genetic MONDO:0011899 Pathograph 5 Show in embeddings browser RASopathy

Noonan syndrome-like disorder with loose anagen hair (NS/LAH, also called Mazzanti syndrome) is an autosomal dominant RASopathy of the RAS-MAPK pathway that clinically overlaps Noonan syndrome but is distinguished by a characteristic ectodermal hair anomaly, loose anagen hair (easily pluckable, sparse, thin, and slow-growing hair with an abnormal hair bulb lacking root sheaths). Cardinal features include Noonan-like facial dysmorphism, short stature frequently associated with growth hormone deficiency, relative macrocephaly with enlarged cerebrospinal fluid spaces, congenital heart defects, darkly pigmented and hyperkeratotic skin, and a distinctive behavioral/developmental profile including attention deficit-hyperactivity disorder. Type 1 (NSLH1) is caused by a single recurrent SHOC2 mutation (p.Ser2Gly) that introduces an aberrant N-myristoylation site; a phenotypically similar type 2 (NSLH2) is caused by recurrent de novo PPP1CB mutations. The condition is very rare, with only a few dozen molecularly confirmed cases reported.

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1
Mappings
1
Inheritance
3
Pathophys.
13
Phenotypes
5
Pathograph
2
Genes
3
Medical Actions
2
Subtypes
🔗

Mappings

MONDO
MONDO:0011899 Noonan syndrome-like disorder with loose anagen hair
skos:exactMatch MONDO
Primary disease term for this entry.
👪

Inheritance

1
Autosomal Dominant HP:0000006
NS/LAH is inherited in an autosomal dominant manner. Cases typically arise from de novo mutations (the recurrent SHOC2 p.Ser2Gly in NSLH1 and recurrent de novo PPP1CB mutations in NSLH2).
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Exome sequencing identified de novo heterozygous missense mutations in PPP1CB in all four patients."
Heterozygous de novo mutations are consistent with autosomal dominant inheritance.
◆

Subtypes

2
NSLH1 (SHOC2-related, Mazzanti syndrome) MONDO:0054637
SHOC2 hgnc:15454 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SHOC2 (hgnc:15454). hgnc:15454 is a gene from the HUGO Gene Nomenclature Committee.
Caused by the single recurrent SHOC2 c.4A>G (p.Ser2Gly) missense mutation. This is the classic, most frequently reported form (Mazzanti syndrome), with the most consistent loose anagen hair and growth hormone deficiency.
Show evidence (1 reference)
PMID:19684605 SUPPORT Human Clinical
"Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721) shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution)"
Establishes the single recurrent SHOC2 p.Ser2Gly mutation as the cause of NSLH1.
NSLH2 (PPP1CB-related) MONDO:0054588
PPP1CB hgnc:9282 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PPP1CB (hgnc:9282). hgnc:9282 is a gene from the HUGO Gene Nomenclature Committee.
Caused by recurrent de novo missense mutations in PPP1CB (most commonly p.Pro49Arg). Phenotypically most similar to NSLH1 but growth hormone deficiency appears less consistent.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Here we report on four unrelated patients with de novo missense mutations in protein phosphatase 1 catalytic subunit beta (PPP1CB) (OMIM#600590), who share a recognizable phenotype consistent with a rasopathy and most similar to NS-LAH."
Establishes PPP1CB as a second locus producing an NS/LAH-like phenotype (NSLH2).
⚙

Pathophysiology

3
Aberrant SHOC2 N-Myristoylation
The recurrent SHOC2 p.Ser2Gly substitution creates a novel N-terminal glycine that introduces an aberrant N-myristoylation site. This acquired lipid modification mistargets SHOC2 (a leucine-rich repeat scaffold that positively modulates RAS-MAPK signaling) to the plasma membrane and impairs its growth-factor-stimulated translocation to the nucleus, dysregulating signal flow through the pathway.
SHOC2 hgnc:15454 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SHOC2 (hgnc:15454). hgnc:15454 is a gene from the HUGO Gene Nomenclature Committee.
aberrant N-terminal protein myristoylation GO:0006499 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal aberrant N-terminal protein myristoylation, annotated with N-terminal protein myristoylation (GO:0006499). GO:0006499 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
RAS-MAPK Pathway Dysregulation Mislocalized, constitutively membrane-anchored SHOC2(S2G) enhances MAPK activation, driving RASopathy phenotypes.
Show evidence (1 reference)
PMID:19684605 SUPPORT Human Clinical
"shared the 4A>G missense change in SHOC2 (producing an S2G amino acid substitution) that introduces an N-myristoylation site, resulting in aberrant targeting of SHOC2 to the plasma membrane and impaired translocation to the nucleus upon growth factor stimulation"
Describes the molecular consequence of the SHOC2 p.Ser2Gly mutation: aberrant N-myristoylation causing mislocalization.
PP1C-SHOC2 Complex Dysregulation of RAF Dephosphorylation
SHOC2 forms a complex with the catalytic subunit of protein phosphatase 1 (PP1C, whose beta isoform is encoded by PPP1CB). Upon stimulation by MRAS, the PP1C-SHOC2 holophosphatase dephosphorylates RAF kinases at an inhibitory serine (RAF1 Ser259), relieving autoinhibition and promoting ERK cascade activation. Recurrent PPP1CB missense mutations are predicted to enhance this RAF-activating dephosphorylation, providing a molecular correlate for the phenotypic similarity between PPP1CB- and SHOC2-related NS/LAH.
PPP1CB hgnc:9282 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PPP1CB (hgnc:9282). hgnc:9282 is a gene from the HUGO Gene Nomenclature Committee. SHOC2 hgnc:15454 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SHOC2 (hgnc:15454). hgnc:15454 is a gene from the HUGO Gene Nomenclature Committee.
protein serine/threonine phosphatase activity GO:0004722 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves protein serine/threonine phosphatase activity (GO:0004722). GO:0004722 is a molecular function from the Gene Ontology.
Downstream
RAS-MAPK Pathway Dysregulation Enhanced dephosphorylation of the inhibitory RAF serine by the mutant PP1C-SHOC2 complex sustains RAF-to-ERK signaling.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation, the fourth had a c.166G>C, p.Ala56Pro change."
Documents the recurrent PPP1CB missense mutations underlying NSLH2.
RAS-MAPK Pathway Dysregulation
Like other RASopathies, NS/LAH results from germline dysregulation of the RAS-MAPK (RAS/ERK) signal transduction pathway, producing prolonged pathway activation with increased phosphorylation of downstream effectors MEK and ERK. This shared final common mechanism underlies the multisystem developmental phenotype.
positive regulation of MAPK cascade GO:0043410 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of MAPK cascade (GO:0043410). GO:0043410 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Pathogenic mutations alter regulatory protein-protein interactions within the pathway, resulting in prolonged RAS/MAPK pathway activation with increased phosphorylation of downstream effectors, MEK and ERK."
Describes the shared RAS-MAPK hyperactivation mechanism common to the RASopathies, including NS/LAH.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Noonan Syndrome-like Disorder with Loose Anagen Hair Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

13
Cardiovascular 1
Pulmonic Stenosis HP:0001642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonic stenosis (HP:0001642). HP:0001642 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"two had mild defects (mitral valve thickening in Patient 1 and mild pulmonic valve stenosis in Patient 3)"
Documents pulmonic valve stenosis among the congenital heart defects in NS/LAH.
Eye 1
Hypertelorism HP:0000316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertelorism (HP:0000316). HP:0000316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Short stature, feeding difficulties and apparent or documented hypertelorism were present in three."
Hypertelorism is part of the Noonan-like facial phenotype in NS/LAH.
Head and Neck 1
Macrocephaly HP:0000256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocephaly (HP:0000256). HP:0000256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12673660 SUPPORT Human Clinical
"short stature, the same facial phenotype, macrocephaly, enlarged cerebral spinal fluid spaces"
Macrocephaly with enlarged CSF spaces is described in NS/LAH.
Integument 2
Sparse Hair HP:0008070 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse hair (HP:0008070). HP:0008070 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Loose anagen hair presents with easily pluckable, sparse, thin and slow growing hair"
Sparse hair is a component of the loose anagen hair phenotype.
Hyperpigmentation of the Skin HP:0000953 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperpigmentation of the skin (HP:0000953). HP:0000953 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12673660 SUPPORT Human Clinical
"GH deficiency, darkly pigmented and hairless skin, and the unusual aspect of the hair"
Darkly pigmented skin is part of the ectodermal phenotype of NS/LAH.
Nervous System 2
Global Developmental Delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Delayed development, relative or absolute macrocephaly, hair abnormalities and low-set, posteriorly angulated ears were seen in all four individuals."
Developmental delay is a consistent neurodevelopmental feature.
Attention Deficit Hyperactivity Disorder HP:0007018 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Attention deficit hyperactivity disorder (HP:0007018). HP:0007018 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12673660 SUPPORT Human Clinical
"mild psychomotor delay with attention deficit/hyperactivity disorder (ADHD)"
ADHD is part of the distinctive behavioral phenotype of NS/LAH.
Growth 1
Short Stature HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12673660 SUPPORT Human Clinical
"We present three children with short stature, the same facial phenotype, macrocephaly, enlarged cerebral spinal fluid spaces"
Short stature is a cardinal feature in the original clinical description.
Other 5
Loose Anagen Hair HP:0040169 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Loose anagen hair (HP:0040169). HP:0040169 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Loose anagen hair presents with easily pluckable, sparse, thin and slow growing hair with an irregular texture caused by an abnormal hair bulb lacking inner and outer root sheaths."
Defines the characteristic loose anagen hair anomaly that distinguishes NS/LAH.
Slow-Growing Hair HP:0002217 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Slow-growing hair (HP:0002217). HP:0002217 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Very slow growing hair with a fine or unruly hair texture was seen in three individuals"
Slow-growing hair is characteristic of the NS/LAH ectodermal phenotype.
Growth Hormone Deficiency Decreased response to growth hormone stimulation test HP:0000824 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Growth hormone deficiency, annotated with Decreased response to growth hormone stimulation test (HP:0000824). HP:0000824 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24124081 SUPPORT Human Clinical
"Cardinal features include facial features resembling NS, short stature often associated with proven growth hormone deficiency (GHD), typical ectodermal anomalies, and distinctive behavior."
Growth hormone deficiency is a cardinal feature of NS/LAH.
Low-Set, Posteriorly Rotated Ears HP:0000358 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Low-set, posteriorly rotated ears, annotated with Posteriorly rotated ears (HP:0000358). HP:0000358 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Delayed development, relative or absolute macrocephaly, hair abnormalities and low-set, posteriorly angulated ears were seen in all four individuals."
Low-set, posteriorly rotated ears are part of the facial phenotype.
Chiari Type I Malformation HP:0007099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chiari type I malformation (HP:0007099). HP:0007099 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Patient 1 had cerebellar tonsillar ectopia progressing to Chiari 1 malformation, Chiari 1 malformation has been reported in several individuals with NS-LAH"
Chiari type I malformation is a reported CNS feature of NS/LAH.
🧬

Genetic Associations

2
SHOC2 (Pathogenic Variants)
Gene: SHOC2 hgnc:15454 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SHOC2 (hgnc:15454). hgnc:15454 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Noonan syndrome with loose anagen hair is caused exclusively by a single recurrent missense mutation in SHOC2, p.Ser2Gly"
Confirms the single recurrent SHOC2 p.Ser2Gly mutation as the cause of NSLH1.
PPP1CB (Pathogenic Variants)
Gene: PPP1CB hgnc:9282 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PPP1CB (hgnc:9282). hgnc:9282 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:27264673 SUPPORT Human Clinical
"Exome sequencing identified de novo heterozygous missense mutations in PPP1CB in all four patients."
Confirms de novo PPP1CB missense mutations as the cause of NSLH2.
💊

Medical Actions

3
Growth Hormone (Somatropin) Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Long-term recombinant growth hormone therapy is used for the frequently associated growth hormone deficiency and short stature; patients benefit, although without the catch-up growth of isolated GH deficiency.
Show evidence (1 reference)
PMID:24124081 SUPPORT Human Clinical
"our data in this small cohort suggest that NS/LAH patients benefit from long-term GH-therapy, although they do not show the characteristic catch-up growth of isolated GHD"
Supports growth hormone therapy as a management option in NS/LAH.
Supportive and Multidisciplinary Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management is largely supportive and symptom-directed, including cardiology surveillance, developmental/behavioral support, and monitoring for neurological (e.g., Chiari I) complications.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling for the affected individual and family, given autosomal dominant inheritance with predominantly de novo occurrence.
📊

Prevalence

1
Worldwide
Cases In Literature Unknown
NS/LAH is very rare; the seminal SHOC2 study identified 25 subjects sharing the recurrent mutation, and only a few dozen molecularly confirmed cases have been reported.
Show evidence (1 reference)
PMID:19684605 SUPPORT Human Clinical
"Twenty-five subjects with a relatively consistent phenotype previously termed Noonan-like syndrome with loose anagen hair (MIM607721) shared the 4A>G missense change in SHOC2"
Reports the number of affected subjects in the defining cohort.
{ }

Source YAML

click to show 
name: Noonan Syndrome-like Disorder with Loose Anagen Hair
creation_date: "2026-07-12T00:00:00Z"
description: >-
  Noonan syndrome-like disorder with loose anagen hair (NS/LAH, also called
  Mazzanti syndrome) is an autosomal dominant RASopathy of the RAS-MAPK pathway
  that clinically overlaps Noonan syndrome but is distinguished by a characteristic
  ectodermal hair anomaly, loose anagen hair (easily pluckable, sparse, thin, and
  slow-growing hair with an abnormal hair bulb lacking root sheaths). Cardinal
  features include Noonan-like facial dysmorphism, short stature frequently
  associated with growth hormone deficiency, relative macrocephaly with enlarged
  cerebrospinal fluid spaces, congenital heart defects, darkly pigmented and
  hyperkeratotic skin, and a distinctive behavioral/developmental profile including
  attention deficit-hyperactivity disorder. Type 1 (NSLH1) is caused by a single
  recurrent SHOC2 mutation (p.Ser2Gly) that introduces an aberrant N-myristoylation
  site; a phenotypically similar type 2 (NSLH2) is caused by recurrent de novo
  PPP1CB mutations. The condition is very rare, with only a few dozen molecularly
  confirmed cases reported.
category: Genetic
parents:
- RASopathy
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0011899
      label: Noonan syndrome-like disorder with loose anagen hair
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary disease term for this entry.
disease_term:
  preferred_term: Noonan syndrome-like disorder with loose anagen hair
  description: >-
    A RASopathy clinically overlapping Noonan syndrome and distinguished by loose
    anagen hair, caused by dysregulated RAS-MAPK signaling.
  term:
    id: MONDO:0011899
    label: Noonan syndrome-like disorder with loose anagen hair
has_subtypes:
- name: NSLH1
  display_name: NSLH1 (SHOC2-related, Mazzanti syndrome)
  subtype_term:
    preferred_term: Noonan syndrome-like disorder with loose anagen hair 1
    term:
      id: MONDO:0054637
      label: Noonan syndrome-like disorder with loose anagen hair 1
  description: >-
    Caused by the single recurrent SHOC2 c.4A>G (p.Ser2Gly) missense mutation.
    This is the classic, most frequently reported form (Mazzanti syndrome), with
    the most consistent loose anagen hair and growth hormone deficiency.
  genes:
  - preferred_term: SHOC2
    term:
      id: hgnc:15454
      label: SHOC2
  evidence:
  - reference: PMID:19684605
    reference_title: "Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-five subjects with a relatively consistent phenotype previously
      termed Noonan-like syndrome with loose anagen hair (MIM607721) shared the
      4A>G missense change in SHOC2 (producing an S2G amino acid substitution)
    explanation: >-
      Establishes the single recurrent SHOC2 p.Ser2Gly mutation as the cause of
      NSLH1.
- name: NSLH2
  display_name: NSLH2 (PPP1CB-related)
  subtype_term:
    preferred_term: Noonan syndrome-like disorder with loose anagen hair 2
    term:
      id: MONDO:0054588
      label: Noonan syndrome-like disorder with loose anagen hair 2
  description: >-
    Caused by recurrent de novo missense mutations in PPP1CB (most commonly
    p.Pro49Arg). Phenotypically most similar to NSLH1 but growth hormone
    deficiency appears less consistent.
  genes:
  - preferred_term: PPP1CB
    term:
      id: hgnc:9282
      label: PPP1CB
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on four unrelated patients with de novo missense mutations
      in protein phosphatase 1 catalytic subunit beta (PPP1CB) (OMIM#600590),
      who share a recognizable phenotype consistent with a rasopathy and most
      similar to NS-LAH.
    explanation: >-
      Establishes PPP1CB as a second locus producing an NS/LAH-like phenotype
      (NSLH2).
pathophysiology:
- name: Aberrant SHOC2 N-Myristoylation
  description: >-
    The recurrent SHOC2 p.Ser2Gly substitution creates a novel N-terminal
    glycine that introduces an aberrant N-myristoylation site. This acquired
    lipid modification mistargets SHOC2 (a leucine-rich repeat scaffold that
    positively modulates RAS-MAPK signaling) to the plasma membrane and impairs
    its growth-factor-stimulated translocation to the nucleus, dysregulating
    signal flow through the pathway.
  genes:
  - preferred_term: SHOC2
    term:
      id: hgnc:15454
      label: SHOC2
  biological_processes:
  - preferred_term: aberrant N-terminal protein myristoylation
    term:
      id: GO:0006499
      label: N-terminal protein myristoylation
    modifier: ABNORMAL
  downstream:
  - target: RAS-MAPK Pathway Dysregulation
    description: >-
      Mislocalized, constitutively membrane-anchored SHOC2(S2G) enhances MAPK
      activation, driving RASopathy phenotypes.
    evidence:
    - reference: PMID:19684605
      reference_title: "Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Expression of SHOC2(S2G) in vitro enhanced MAPK activation in a cell type-specific fashion."
      explanation: >-
        Functional evidence that the aberrant N-myristoylation of SHOC2 enhances
        downstream MAPK signaling.
  evidence:
  - reference: PMID:19684605
    reference_title: "Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      shared the 4A>G missense change in SHOC2 (producing an S2G amino acid
      substitution) that introduces an N-myristoylation site, resulting in
      aberrant targeting of SHOC2 to the plasma membrane and impaired
      translocation to the nucleus upon growth factor stimulation
    explanation: >-
      Describes the molecular consequence of the SHOC2 p.Ser2Gly mutation:
      aberrant N-myristoylation causing mislocalization.
- name: PP1C-SHOC2 Complex Dysregulation of RAF Dephosphorylation
  description: >-
    SHOC2 forms a complex with the catalytic subunit of protein phosphatase 1
    (PP1C, whose beta isoform is encoded by PPP1CB). Upon stimulation by MRAS,
    the PP1C-SHOC2 holophosphatase dephosphorylates RAF kinases at an inhibitory
    serine (RAF1 Ser259), relieving autoinhibition and promoting ERK cascade
    activation. Recurrent PPP1CB missense mutations are predicted to enhance this
    RAF-activating dephosphorylation, providing a molecular correlate for the
    phenotypic similarity between PPP1CB- and SHOC2-related NS/LAH.
  genes:
  - preferred_term: PPP1CB
    term:
      id: hgnc:9282
      label: PPP1CB
  - preferred_term: SHOC2
    term:
      id: hgnc:15454
      label: SHOC2
  molecular_functions:
  - preferred_term: protein serine/threonine phosphatase activity
    term:
      id: GO:0004722
      label: protein serine/threonine phosphatase activity
  downstream:
  - target: RAS-MAPK Pathway Dysregulation
    description: >-
      Enhanced dephosphorylation of the inhibitory RAF serine by the mutant
      PP1C-SHOC2 complex sustains RAF-to-ERK signaling.
    evidence:
    - reference: PMID:27264673
      reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        PP1C and SHOC2 form a complex which, after stimulation by MRAS,
        dephosphorylates RAFs at an inhibitory serine, resulting in activation of
        the signaling cascade
      explanation: >-
        Describes the PP1C-SHOC2 mechanism linking PPP1CB to RAF activation and
        downstream MAPK signaling.
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three individuals had the recurrent PPP1CB c.146G>C, p.Pro49Arg mutation,
      the fourth had a c.166G>C, p.Ala56Pro change.
    explanation: >-
      Documents the recurrent PPP1CB missense mutations underlying NSLH2.
- name: RAS-MAPK Pathway Dysregulation
  description: >-
    Like other RASopathies, NS/LAH results from germline dysregulation of the
    RAS-MAPK (RAS/ERK) signal transduction pathway, producing prolonged pathway
    activation with increased phosphorylation of downstream effectors MEK and
    ERK. This shared final common mechanism underlies the multisystem
    developmental phenotype.
  biological_processes:
  - preferred_term: positive regulation of MAPK cascade
    term:
      id: GO:0043410
      label: positive regulation of MAPK cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic mutations alter regulatory protein-protein interactions within
      the pathway, resulting in prolonged RAS/MAPK pathway activation with
      increased phosphorylation of downstream effectors, MEK and ERK.
    explanation: >-
      Describes the shared RAS-MAPK hyperactivation mechanism common to the
      RASopathies, including NS/LAH.
phenotypes:
- name: Loose Anagen Hair
  description: >-
    The defining ectodermal feature: easily pluckable, sparse, thin, and slow-growing
    hair of irregular texture, caused by an abnormal hair bulb lacking inner and
    outer root sheaths.
  phenotype_term:
    preferred_term: Loose anagen hair
    term:
      id: HP:0040169
      label: Loose anagen hair
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loose anagen hair presents with easily pluckable, sparse, thin and slow
      growing hair with an irregular texture caused by an abnormal hair bulb
      lacking inner and outer root sheaths.
    explanation: >-
      Defines the characteristic loose anagen hair anomaly that distinguishes
      NS/LAH.
- name: Sparse Hair
  phenotype_term:
    preferred_term: Sparse hair
    term:
      id: HP:0008070
      label: Sparse hair
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Loose anagen hair presents with easily pluckable, sparse, thin and slow
      growing hair
    explanation: Sparse hair is a component of the loose anagen hair phenotype.
- name: Slow-Growing Hair
  phenotype_term:
    preferred_term: Slow-growing hair
    term:
      id: HP:0002217
      label: Slow-growing hair
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Very slow growing hair with a fine or unruly hair texture was seen in
      three individuals
    explanation: Slow-growing hair is characteristic of the NS/LAH ectodermal phenotype.
- name: Short Stature
  description: >-
    Short stature is common and, in SHOC2-related disease, frequently associated
    with growth hormone deficiency.
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:12673660
    reference_title: "Noonan-like syndrome with loose anagen hair: a new syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present three children with short stature, the same facial phenotype,
      macrocephaly, enlarged cerebral spinal fluid spaces
    explanation: Short stature is a cardinal feature in the original clinical description.
- name: Growth Hormone Deficiency
  description: >-
    Severe growth hormone deficiency is characteristic of SHOC2-related NS/LAH and
    contributes to the short stature.
  phenotype_term:
    preferred_term: Growth hormone deficiency
    term:
      id: HP:0000824
      label: Decreased response to growth hormone stimulation test
  evidence:
  - reference: PMID:24124081
    reference_title: "GH Therapy and first final height data in Noonan-like syndrome with loose anagen hair (Mazzanti syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardinal features include facial features resembling NS, short stature
      often associated with proven growth hormone deficiency (GHD), typical
      ectodermal anomalies, and distinctive behavior.
    explanation: Growth hormone deficiency is a cardinal feature of NS/LAH.
- name: Macrocephaly
  description: Relative or absolute macrocephaly, often with mildly enlarged ventricles and cerebrospinal fluid spaces.
  phenotype_term:
    preferred_term: Macrocephaly
    term:
      id: HP:0000256
      label: Macrocephaly
  evidence:
  - reference: PMID:12673660
    reference_title: "Noonan-like syndrome with loose anagen hair: a new syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      short stature, the same facial phenotype, macrocephaly, enlarged cerebral
      spinal fluid spaces
    explanation: Macrocephaly with enlarged CSF spaces is described in NS/LAH.
- name: Hypertelorism
  phenotype_term:
    preferred_term: Hypertelorism
    term:
      id: HP:0000316
      label: Hypertelorism
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Short stature, feeding difficulties and apparent or documented
      hypertelorism were present in three.
    explanation: Hypertelorism is part of the Noonan-like facial phenotype in NS/LAH.
- name: Low-Set, Posteriorly Rotated Ears
  phenotype_term:
    preferred_term: Low-set, posteriorly rotated ears
    term:
      id: HP:0000358
      label: Posteriorly rotated ears
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Delayed development, relative or absolute macrocephaly, hair abnormalities
      and low-set, posteriorly angulated ears were seen in all four individuals.
    explanation: Low-set, posteriorly rotated ears are part of the facial phenotype.
- name: Pulmonic Stenosis
  description: Congenital heart defects occur, including pulmonic valve stenosis and mitral valve anomalies.
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      two had mild defects (mitral valve thickening in Patient 1 and mild
      pulmonic valve stenosis in Patient 3)
    explanation: Documents pulmonic valve stenosis among the congenital heart defects in NS/LAH.
- name: Global Developmental Delay
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Delayed development, relative or absolute macrocephaly, hair abnormalities
      and low-set, posteriorly angulated ears were seen in all four individuals.
    explanation: Developmental delay is a consistent neurodevelopmental feature.
- name: Attention Deficit Hyperactivity Disorder
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:12673660
    reference_title: "Noonan-like syndrome with loose anagen hair: a new syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      mild psychomotor delay with attention deficit/hyperactivity disorder
      (ADHD)
    explanation: ADHD is part of the distinctive behavioral phenotype of NS/LAH.
- name: Hyperpigmentation of the Skin
  description: Darkly pigmented skin with ectodermal anomalies including hyperkeratosis, keratosis pilaris, and eczema.
  phenotype_term:
    preferred_term: Hyperpigmentation of the skin
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: PMID:12673660
    reference_title: "Noonan-like syndrome with loose anagen hair: a new syndrome?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      GH deficiency, darkly pigmented and hairless skin, and the unusual aspect
      of the hair
    explanation: Darkly pigmented skin is part of the ectodermal phenotype of NS/LAH.
- name: Chiari Type I Malformation
  description: Relative macrocephaly can be accompanied by cerebellar tonsillar ectopia progressing to Chiari type I malformation.
  phenotype_term:
    preferred_term: Chiari type I malformation
    term:
      id: HP:0007099
      label: Chiari type I malformation
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1 had cerebellar tonsillar ectopia progressing to Chiari 1
      malformation, Chiari 1 malformation has been reported in several
      individuals with NS-LAH
    explanation: Chiari type I malformation is a reported CNS feature of NS/LAH.
genetic:
- name: SHOC2
  gene_term:
    preferred_term: SHOC2
    term:
      id: hgnc:15454
      label: SHOC2
  association: Pathogenic Variants
  notes: >-
    NSLH1 is caused exclusively by the single recurrent SHOC2 c.4A>G (p.Ser2Gly)
    missense mutation, which introduces an aberrant N-myristoylation site. SHOC2
    encodes a leucine-rich repeat scaffold that positively regulates RAS-MAPK
    signaling as a regulatory subunit of protein phosphatase 1.
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Noonan syndrome with loose anagen hair is caused exclusively by a single
      recurrent missense mutation in SHOC2, p.Ser2Gly
    explanation: Confirms the single recurrent SHOC2 p.Ser2Gly mutation as the cause of NSLH1.
- name: PPP1CB
  gene_term:
    preferred_term: PPP1CB
    term:
      id: hgnc:9282
      label: PPP1CB
  association: Pathogenic Variants
  notes: >-
    NSLH2 is caused by recurrent de novo missense mutations in PPP1CB, most
    commonly p.Pro49Arg. PPP1CB encodes the beta catalytic subunit of protein
    phosphatase 1, which partners with SHOC2 to dephosphorylate and activate RAF.
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified de novo heterozygous missense mutations in
      PPP1CB in all four patients.
    explanation: Confirms de novo PPP1CB missense mutations as the cause of NSLH2.
inheritance:
- name: Autosomal Dominant
  description: >-
    NS/LAH is inherited in an autosomal dominant manner. Cases typically arise
    from de novo mutations (the recurrent SHOC2 p.Ser2Gly in NSLH1 and recurrent
    de novo PPP1CB mutations in NSLH2).
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:27264673
    reference_title: "A novel rasopathy caused by recurrent de novo missense mutations in PPP1CB closely resembles Noonan syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing identified de novo heterozygous missense mutations in
      PPP1CB in all four patients.
    explanation: >-
      Heterozygous de novo mutations are consistent with autosomal dominant
      inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    NS/LAH is very rare; the seminal SHOC2 study identified 25 subjects sharing
    the recurrent mutation, and only a few dozen molecularly confirmed cases have
    been reported.
  evidence:
  - reference: PMID:19684605
    reference_title: "Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twenty-five subjects with a relatively consistent phenotype previously
      termed Noonan-like syndrome with loose anagen hair (MIM607721) shared the
      4A>G missense change in SHOC2
    explanation: Reports the number of affected subjects in the defining cohort.
treatments:
- name: Growth Hormone (Somatropin) Therapy
  description: >-
    Long-term recombinant growth hormone therapy is used for the frequently
    associated growth hormone deficiency and short stature; patients benefit,
    although without the catch-up growth of isolated GH deficiency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:24124081
    reference_title: "GH Therapy and first final height data in Noonan-like syndrome with loose anagen hair (Mazzanti syndrome)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our data in this small cohort suggest that NS/LAH patients benefit from
      long-term GH-therapy, although they do not show the characteristic catch-up
      growth of isolated GHD
    explanation: Supports growth hormone therapy as a management option in NS/LAH.
- name: Supportive and Multidisciplinary Care
  description: >-
    Management is largely supportive and symptom-directed, including
    cardiology surveillance, developmental/behavioral support, and monitoring for
    neurological (e.g., Chiari I) complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: Genetic counseling for the affected individual and family, given autosomal dominant inheritance with predominantly de novo occurrence.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling