Hypopigmentation-punctate palmoplantar keratoderma syndrome

Summary

Hypopigmentation-punctate palmoplantar keratoderma syndrome (MONDO:0014227) is a disease caused by ENPP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ENPP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 136

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hypopigmentation-punctate palmoplantar keratoderma syndrome
Mondo ID	MONDO:0014227
OMIM	615522
Orphanet	324561
SNOMED CT	711154007
UMLS	C3809781
MedGen	816111
GARD	0012384
Is cancer (heuristic)	no

Also known as: COLE disease · Cole disease · COLED · guttate hypopigmentation · guttate hypopigmentation and punctate palmoplantar keratoderma · hypopigmentation and punctate keratosis of the palms and soles · punctate palmoplantar keratoderma with or without ectopic calcification

Data availability: 136 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › hypopigmentation-punctate palmoplantar keratoderma syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

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

136 retrieved; paginated sample, class counts are floors:

88 uncertain significance, 14 conflicting classifications of pathogenicity, 11 likely pathogenic, 7 likely benign, 7 pathogenic, 5 pathogenic/likely pathogenic, 2 benign/likely benign, 2 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179191	NM_006208.3(ENPP1):c.2344C>T (p.Arg782Ter)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1685769	NM_006208.3(ENPP1):c.1366C>T (p.Arg456Ter)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
282087	NM_006208.3(ENPP1):c.1756G>A (p.Gly586Arg)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29842	NM_006208.3(ENPP1):c.913C>A (p.Pro305Thr)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2991390	NM_006208.3(ENPP1):c.2631G>A (p.Trp877Ter)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593055	NM_006208.3(ENPP1):c.313+1G>A	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593077	NM_006208.3(ENPP1):c.1426C>T (p.Arg476Ter)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
3593097	NM_006208.3(ENPP1):c.2375A>G (p.Asn792Ser)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
547983	NM_006208.3(ENPP1):c.1441C>T (p.Arg481Trp)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
88750	NM_006208.3(ENPP1):c.530G>A (p.Cys177Tyr)	ENPP1	Pathogenic	no assertion criteria provided
88751	NM_006208.3(ENPP1):c.491G>C (p.Cys164Ser)	ENPP1	Pathogenic	no assertion criteria provided
88752	NM_006208.3(ENPP1):c.446G>C (p.Cys149Ser)	ENPP1	Pathogenic	no assertion criteria provided
3593042	NM_006208.3(ENPP1):c.2T>G (p.Met1Arg)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593043	NM_006208.3(ENPP1):c.6del (p.Glu2fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593047	NM_006208.3(ENPP1):c.124del (p.Asp42fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593067	NM_006208.3(ENPP1):c.769_770del (p.Phe257fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593080	NM_006208.3(ENPP1):c.1709A>G (p.Tyr570Cys)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593095	NM_006208.3(ENPP1):c.2312-1G>A	ENPP1	Likely pathogenic	criteria provided, single submitter
3593103	NM_006208.3(ENPP1):c.2479_2482dup (p.Pro828fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593105	NM_006208.3(ENPP1):c.2596G>A (p.Glu866Lys)	ENPP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779613	NM_006208.3(ENPP1):c.1186del (p.Val396fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
3779614	NM_006208.3(ENPP1):c.2026C>T (p.Gln676Ter)	ENPP1	Likely pathogenic	criteria provided, single submitter
445386	NM_006208.3(ENPP1):c.2608-1G>A	ENPP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
13589	NM_006208.3(ENPP1):c.517A>C (p.Lys173Gln)	ENPP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1397275	NM_006208.3(ENPP1):c.1352A>G (p.Tyr451Cys)	ENPP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1431808	NM_006208.3(ENPP1):c.2114C>T (p.Thr705Met)	ENPP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2888351	NM_006208.3(ENPP1):c.1743G>A (p.Pro581=)	ENPP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2957034	NM_006208.3(ENPP1):c.2625C>T (p.Ser875=)	ENPP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2983301	NM_006208.3(ENPP1):c.34C>G (p.Arg12Gly)	ENPP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3275471	NM_006208.3(ENPP1):c.1962T>A (p.His654Gln)	ENPP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · 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
ENPP1	Strong	Autosomal dominant	hypopigmentation-punctate palmoplantar keratoderma syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ENPP1	Orphanet:289176	Autosomal recessive hypophosphatemic rickets
ENPP1	Orphanet:324561	Hypopigmentation-punctate palmoplantar keratoderma syndrome
ENPP1	Orphanet:51608	Generalized arterial calcification of infancy
ENPP1	Orphanet:758	Pseudoxanthoma elasticum

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ENPP1	HGNC:3356	ENSG00000197594	P22413	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ENPP1	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ENPP1	Phosphatase	yes	3.6.1.9	Somatomedin_B_dom, Endo_G_ENPP1-like_dom, Phosphodiest/P_Trfase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
decidua	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ENPP1	227	ubiquitous	marker	tibia, decidua, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ENPP1	1,911

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ENPP1	P22413	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin B2 (riboflavin) metabolism	1	1631.4×	0.001	ENPP1
Vitamin B5 (pantothenate) metabolism	1	761.3×	0.001	ENPP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete negative regulation of hh target transcription factor activity	1	16852.0×	0.001	ENPP1
inorganic diphosphate transport	1	8426.0×	0.001	ENPP1
nucleoside triphosphate catabolic process	1	3370.4×	0.002	ENPP1
nucleic acid metabolic process	1	2808.7×	0.002	ENPP1
negative regulation of glycogen biosynthetic process	1	2106.5×	0.002	ENPP1
intracellular phosphate ion homeostasis	1	1532.0×	0.002	ENPP1
negative regulation of D-glucose import across plasma membrane	1	1203.7×	0.002	ENPP1
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1	1123.5×	0.002	ENPP1
phosphate ion homeostasis	1	1053.2×	0.002	ENPP1
phosphate-containing compound metabolic process	1	991.3×	0.002	ENPP1
response to ATP	1	991.3×	0.002	ENPP1
negative regulation of bone mineralization	1	936.2×	0.002	ENPP1
melanocyte differentiation	1	802.5×	0.002	ENPP1
regulation of bone mineralization	1	732.7×	0.002	ENPP1
ATP metabolic process	1	468.1×	0.003	ENPP1
negative regulation of insulin receptor signaling pathway	1	374.5×	0.004	ENPP1
generation of precursor metabolites and energy	1	343.9×	0.004	ENPP1
negative regulation of fat cell differentiation	1	312.1×	0.004	ENPP1
bone mineralization	1	271.8×	0.004	ENPP1
cellular response to insulin stimulus	1	170.2×	0.007	ENPP1
negative regulation of cell growth	1	144.0×	0.008	ENPP1
gene expression	1	79.9×	0.013	ENPP1
immune response	1	47.1×	0.021	ENPP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ENPP1	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	ENPP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ENPP1	167	Binding:154, ADMET:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENPP1	3.6.1.9	nucleotide diphosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ENPP1	167

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
SURAMIN	3	ENPP1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ENPP1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.