Noonan syndrome-like disorder with loose anagen hair

Summary

Noonan syndrome-like disorder with loose anagen hair (MONDO:0011899) is a disease caused by variants in PPP1CB and SHOC2, with 3 cohort genes. The dominant Reactome pathway is RAF activation (3 cohort genes).

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: PPP1CB (GenCC Definitive), SHOC2 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 5
• Phenotypes (HPO): 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		70	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

29 HPO clinical features (Orphanet curated; top 29 by frequency):

HPO ID	Term	Frequency
HP:0000465	Webbed neck	Very frequent (80-99%)
HP:0002162	Low posterior hairline	Very frequent (80-99%)
HP:0002209	Sparse scalp hair	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000238	Hydrocephalus	Frequent (30-79%)
HP:0000286	Epicanthus	Frequent (30-79%)
HP:0000400	Macrotia	Frequent (30-79%)
HP:0000463	Anteverted nares	Frequent (30-79%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001639	Hypertrophic cardiomyopathy	Frequent (30-79%)
HP:0001642	Pulmonic stenosis	Frequent (30-79%)
HP:0002002	Deep philtrum	Frequent (30-79%)
HP:0100840	Aplasia/Hypoplasia of the eyebrow	Frequent (30-79%)
HP:0000028	Cryptorchidism	Occasional (5-29%)
HP:0000174	Abnormal palate morphology	Occasional (5-29%)
HP:0000179	Thick lower lip vermilion	Occasional (5-29%)
HP:0000233	Thin vermilion border	Occasional (5-29%)
HP:0000316	Hypertelorism	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000670	Carious teeth	Occasional (5-29%)
HP:0001156	Brachydactyly	Occasional (5-29%)
HP:0001231	Abnormal fingernail morphology	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001800	Hypoplastic toenails	Occasional (5-29%)
HP:0005108	Abnormal intervertebral disk morphology	Occasional (5-29%)
HP:0009811	Abnormality of the elbow	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Noonan syndrome-like disorder with loose anagen hair
Mondo ID	MONDO:0011899
MeSH	C564342
OMIM	607721
Orphanet	2701
DOID	DOID:0080691
NCIT	C178129
SNOMED CT	723444009
UMLS	C1843181
MedGen	334697
GARD	0010719
Is cancer (heuristic)	no

Also known as: Noonan syndrome-like disorder with loose anagen hair · Noonan-like syndrome with loose anagen hair · NS/LAH · NSLH · NSLH1 · Tosti syndrome

Data availability: 5 ClinVar variants · 5 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › disorder of pilosebaceous unit › hair anomaly › alopecia › loose anagen syndrome › Noonan syndrome-like disorder with loose anagen hair

Subtypes (2): Noonan syndrome-like disorder with loose anagen hair 2, Noonan syndrome-like disorder with loose anagen hair 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 2 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
254652	NM_002709.3(PPP1CB):c.548A>C (p.Glu183Ala)	PPP1CB	Pathogenic	reviewed by expert panel
6821	NM_007373.4(SHOC2):c.4A>G (p.Ser2Gly)	SHOC2	Pathogenic	reviewed by expert panel
218698	NM_007373.4(SHOC2):c.806A>G (p.Gln269Arg)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
373090	NM_007373.4(SHOC2):c.517A>G (p.Met173Val)	SHOC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3361034	NM_007373.4(SHOC2):c.566A>G (p.Tyr189Cys)	SHOC2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PPP1CB	Definitive	Autosomal dominant	Noonan syndrome-like disorder with loose anagen hair	6
SHOC2	Definitive	Autosomal dominant	Noonan syndrome-like disorder with loose anagen hair	9
HRAS	Disputed Evidence	Autosomal dominant	Noonan syndrome-like disorder with loose anagen hair	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SHOC2	Orphanet:2701	Noonan syndrome-like disorder with loose anagen hair
PPP1CB	Orphanet:2701	Noonan syndrome-like disorder with loose anagen hair
HRAS	Orphanet:146	Differentiated thyroid carcinoma
HRAS	Orphanet:2612	Linear nevus sebaceus syndrome
HRAS	Orphanet:2874	Phakomatosis pigmentokeratotica
HRAS	Orphanet:3071	Costello syndrome
HRAS	Orphanet:79414	Woolly hair nevus

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SHOC2	HGNC:15454	ENSG00000108061	Q9UQ13	Leucine-rich repeat protein SHOC-2	gencc,clinvar
PPP1CB	HGNC:9282	ENSG00000213639	P62140	Serine/threonine-protein phosphatase PP1-beta catalytic subunit	gencc,clinvar
HRAS	HGNC:5173	ENSG00000174775	P01112	GTPase HRas	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SHOC2	Leucine-rich repeat protein SHOC-2	Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway.
PPP1CB	Serine/threonine-protein phosphatase PP1-beta catalytic subunit	Protein phosphatase that associates with over 200 regulatory proteins to form highly specific holoenzymes which dephosphorylate hundreds of biological targets.
HRAS	GTPase HRas	Involved in the activation of Ras protein signal transduction.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Phosphatase	1	28.0×	0.106
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SHOC2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf
PPP1CB	Phosphatase	yes	3.1.3.16	Calcineurin-like_PHP, Ser/Thr-sp_prot-phosphatase, Metallo-depent_PP-like
HRAS	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	2
bone marrow	1
sural nerve	1
amniotic fluid	1
buccal mucosa cell	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SHOC2	299	ubiquitous	marker	calcaneal tendon, sural nerve, bone marrow
PPP1CB	295	ubiquitous	marker	calcaneal tendon, amniotic fluid, buccal mucosa cell
HRAS	139	ubiquitous	marker	skin of abdomen, skin of leg, zone of skin

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HRAS	8,064
SHOC2	2,149
PPP1CB	1,044

Intra-cohort edges

A	B	Sources
HRAS	SHOC2	intact, string_interaction
PPP1CB	SHOC2	intact

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HRAS	P01112	246
SHOC2	Q9UQ13	13

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PPP1CB	P62140	91.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 87. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAF activation	3	335.9×	2e-06	SHOC2, PPP1CB, HRAS
SHOC2 M1731 mutant abolishes MRAS complex function	2	951.7×	4e-05	SHOC2, PPP1CB
Gain-of-function MRAS complexes activate RAF signaling	2	951.7×	4e-05	SHOC2, PPP1CB
Signaling by RAS GAP mutants	1	1268.9×	0.010	HRAS
Signaling by RAS GTPase mutants	1	1268.9×	0.010	HRAS
Signaling by MRAS-complex mutants	1	951.7×	0.010	SHOC2
Activation of RAS in B cells	1	761.3×	0.010	HRAS
RAS signaling downstream of NF1 loss-of-function variants	1	543.8×	0.010	HRAS
Estrogen-stimulated signaling through PRKCZ	1	543.8×	0.010	HRAS
SOS-mediated signalling	1	475.8×	0.010	HRAS
Activated NTRK3 signals through RAS	1	423.0×	0.010	HRAS
EGFR Transactivation by Gastrin	1	380.7×	0.010	HRAS
SHC-related events triggered by IGF1R	1	380.7×	0.010	HRAS
Activated NTRK2 signals through RAS	1	380.7×	0.010	HRAS
MET activates RAS signaling	1	346.1×	0.010	HRAS
Signaling by FGFR4 in disease	1	317.2×	0.010	HRAS
Activated NTRK2 signals through FRS2 and FRS3	1	317.2×	0.010	HRAS
Constitutive Signaling by Overexpressed ERBB2	1	317.2×	0.010	HRAS
p38MAPK events	1	292.8×	0.010	HRAS
Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants	1	292.8×	0.010	HRAS
Signaling by PDGFRA extracellular domain mutants	1	292.8×	0.010	HRAS
PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases	1	271.9×	0.010	HRAS
Phosphorylation and nuclear translocation of the CRY:PER:kinase complex	1	271.9×	0.010	PPP1CB
GRB2 events in EGFR signaling	1	253.8×	0.010	HRAS
Erythropoietin activates RAS	1	253.8×	0.010	HRAS
Signaling by FLT3 ITD and TKD mutants	1	253.8×	0.010	HRAS
Maturation of hRSV A proteins	1	253.8×	0.010	PPP1CB
SHC1 events in ERBB4 signaling	1	237.9×	0.010	HRAS
SHC1 events in EGFR signaling	1	237.9×	0.010	HRAS
Constitutive Signaling by EGFRvIII	1	237.9×	0.010	HRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to growth hormone stimulus	1	5617.3×	0.005	SHOC2
MAPK cascade	2	102.1×	0.005	PPP1CB, HRAS
positive regulation of miRNA metabolic process	1	1872.4×	0.011	HRAS
oncogene-induced cell senescence	1	802.5×	0.016	HRAS
cyclic-GMP-AMP transmembrane import across plasma membrane	1	702.2×	0.016	SHOC2
T-helper 1 type immune response	1	624.1×	0.016	HRAS
negative regulation of neural precursor cell proliferation	1	510.7×	0.016	SHOC2
nerve growth factor signaling pathway	1	432.1×	0.016	SHOC2
Schwann cell development	1	351.1×	0.016	HRAS
regulation of long-term neuronal synaptic plasticity	1	330.4×	0.016	HRAS
positive regulation of ruffle assembly	1	330.4×	0.016	HRAS
positive regulation of Ras protein signal transduction	1	295.6×	0.016	SHOC2
regulation of neurotransmitter receptor localization to postsynaptic specialization membrane	1	295.6×	0.016	HRAS
entrainment of circadian clock by photoperiod	1	244.2×	0.018	PPP1CB
defense response to protozoan	1	200.6×	0.018	HRAS
cellular response to gamma radiation	1	200.6×	0.018	HRAS
positive regulation of protein targeting to membrane	1	187.2×	0.018	HRAS
glycogen metabolic process	1	175.5×	0.018	PPP1CB
positive regulation of wound healing	1	175.5×	0.018	HRAS
regulation of MAPK cascade	1	151.8×	0.020	SHOC2
adipose tissue development	1	133.8×	0.021	HRAS
fibroblast proliferation	1	130.6×	0.021	HRAS
intrinsic apoptotic signaling pathway	1	119.5×	0.022	HRAS
regulation of cell adhesion	1	102.1×	0.023	PPP1CB
positive regulation of fibroblast proliferation	1	98.5×	0.023	HRAS
cellular senescence	1	98.5×	0.023	HRAS
fibroblast growth factor receptor signaling pathway	1	95.2×	0.023	SHOC2
negative regulation of neuron differentiation	1	90.6×	0.023	SHOC2
regulation of circadian rhythm	1	86.4×	0.023	PPP1CB
myelination	1	83.8×	0.023	HRAS

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
HRAS	LONAFARNIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HRAS	4	4
SHOC2	0	0
PPP1CB	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LONAFARNIB	4	HRAS
STALLIMYCIN	2	HRAS
L-778123 FREE BASE	1	HRAS
BMS-214662	1	HRAS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
HRAS	48	Binding:45, Functional:3
PPP1CB	9	Binding:9

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PPP1CB	3.1.3.16	protein-serine/threonine phosphatase
HRAS	3.6.5.2	small monomeric GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

4 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
LONAFARNIB	4	HRAS
STALLIMYCIN	2	HRAS
L-778123 FREE BASE	1	HRAS
BMS-214662	1	HRAS

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HRAS
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PPP1CB
E	Difficult family or no structure, no drug	1	SHOC2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SHOC2	0	—
PPP1CB	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.