Familial Progressive Hyperpigmentation With Or Without Hypopigmentation

1. Disease Information

Overview

FPHH is an autosomal dominant pigmentary genodermatosis in which diffuse, progressive hyperpigmentation — present at birth or appearing in early infancy — enlarges and coalesces with age, in most (not all) patients intermingled with café-au-lait macules (CALMs), lentigines, and hypopigmented ash-leaf macules. It is caused by heterozygous gain-of-function missense variants in KITLG (KIT ligand / stem cell factor) at 12q21.32, which increase melanogenic signalling through the melanocyte KIT receptor.

"Familial progressive hyper- and hypopigmentation (FPHH, MIM 145250) is a rare hereditary skin disorder that is predominantly characterized by progressive, diffuse, partly blotchy hyperpigmented lesions intermingled with scattered hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs)." — Wang J et al. 2021, BMC Med Genomics (PMID:33407466)

"Familial progressive hyperpigmentation (FPH) is an autosomal-dominantly inherited disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age." — Wang ZQ et al. 2009, Am J Hum Genet (PMID:19375057)

The disorder is essentially skin-limited. Nails, hair, teeth, mucosae and internal organs are typically normal ("none of them showed any other skin, nail, hair, teeth, mucosal or systemic diseases" — PMID:33407466), with rare exceptions discussed in §3.

The FPH / FPHH split — important for entry scoping

Two OMIM entities exist and are not the same disease:

Amyere et al. explicitly separate them and place FPH nearer DUH2:

"FPHH is distinct from familial progressive hyperpigmentation (FPH), in which no hypopigmented features are present, and which is phenotypically and histologically closer to Dyschromatosis Universalis Hereditaria 2 (DUH2)." — Amyere et al. 2011, J Invest Dermatol (PMID:21368769)

Complicating this, OMIM folded the original KITLG FPH family (Wang 2009) into #145250, so the "FPH" label in the 2009 paper and the "FPHH" label in later papers refer to the same KITLG allelic entity, while OMIM #614233 (FPH1) is a genetically distinct, still-unsolved locus. The dismech entry should cover the KITLG entity (MONDO:0007771 / OMIM #145250) and record FPH1 as a differential/related-but-distinct concept, not as a subtype.

Identifiers

Note for the curator: Orphanet is programmatically blocked from web fetch, but this repo already ingests Orphadata. just structured-rebuild-orphanet --id 280628 (and --id 79146) will produce quotable ORPHA: cache rows for the definition, prevalence class, HPO frequencies, and gene-disease row — a better evidence source for §3 and §9 than anything available on the open web.

Synonyms

• Familial progressive hyper- and hypopigmentation (FPHH)
• Familial progressive hyperpigmentation with or without hypopigmentation
• Melanosis universalis hereditaria (used as a synonym by GTR and by PMID:39152874)
• Congenital hypomelanotic and hypermelanotic macules (GTR synonym)
• Westerhof syndrome (for the 1978 Hindustani-origin family with growth/mental retardation, PMID:666331)
• Familial progressive hypo- and hyperpigmentation (variant word order used in some case reports)
• Universal melanosis / melanosis diffusa congenita / familial diffuse melanosis (older, loosely applied terms)
• Gene aliases relevant to search: SCF, SF, MGF, KL-1, SLF, SHEP7, DCUA, FPH2, FPHH, DFNA69, WS2F

Evidence provenance

All of it is aggregated disease-level and case/family-level literature. There is no EHR-derived cohort, no registry, and no biobank series for FPHH. Every quantitative statement in this report traces to a single-family report or an in-vitro experiment. This matters for the entry: frequencies are qualitative, and prevalence is undocumented (see §9).

2. Etiology

Primary cause — KITLG gain of function

FPHH is a monogenic, non-environmental, non-infectious disorder. Heterozygous missense variants in KITLG increase the melanogenic output of the KITLG→KIT axis in skin.

"To our knowledge, these data provided the first genetic evidence that the FPH disease is caused by the KITLG N36S mutation, which has a gain-of-function effect on the melanin synthesis" — PMID:19375057

"Most of the FPHH-causing mutations in KITLG are clustered within the conserved VTNNV motif (amino acids 33–37) in exon 2, and a mutated VTNNV domain may increase the affinity of KITLG to the c-Kit receptor, suggesting that the mutation causes a downstream gain-of-function effect." — PMID:33407466

"All the reported mutations affected the residues within the KIT ligand domain, leading to an increased affinity to the kit receptor." — Huang et al. (PMID:39152874)

Locus heterogeneity — a substantial fraction of FPHH is not KITLG

This is a well-documented and under-appreciated feature and should be curated as a knowledge gap:

"However, many FPHH families without KITLG mutations have been identified, indicating additional locus heterogeneity for this disorder" — PMID:33407466

"sequencing analysis did not show any mutation of the KITLG gene in the ten affected individuals" ... the family "provided evidence for genetic heterogeneity of this genodermatosis" — Chinese 4-generation family, 14 affected (PMID:29186243, An Bras Dermatol)

See also the explicitly titled report "Familial progressive hyperpigmentation and hypopigmentation without KITLG mutation" (PMID:27859606; letter, abstract not available in cache — do not use for snippet evidence, cite only for the existence of KITLG-negative families, or better, cite PMID:29186243 which has extractable text).

The unsolved FPH1 locus at 19pter–p13.1 (OMIM 614233) is a second, independent line of evidence for heterogeneity within the broader clinical concept.

Risk factors

• Genetic (causal, not "risk"): a heterozygous KITLG KIT-ligand-domain missense allele is sufficient. There are no reported susceptibility loci or modifier genes for FPHH.
• Family history: the dominant determinant; an affected parent confers 50% transmission risk. But de novo occurrence is well documented (§9), so a negative family history does not exclude the diagnosis.
• Ancestry: case reports are heavily weighted to Han Chinese and Japanese populations, with additional European (Slovenian, Danish, German), Filipino, and Hindustani-origin families. This almost certainly reflects ascertainment and publication bias, not a true founder effect — no shared haplotype has been reported, and the recurrent alleles (p.Thr34Ile, p.Asn36Ser) are at CpG-poor but structurally constrained residues where recurrence is expected from a mutational hotspot, not descent.
• Environmental: none identified. Not toxin-, radiation-, drug-, or occupation-related. Age is not a risk factor for onset (congenital/infantile) but is the driver of lesion accumulation (§8).
• Sex: no sex bias reported; both sexes affected in every pedigree (e.g. seven affected — three men, four women — in family 1 of PMID:33407466; 9 men and 5 women in the KITLG-negative family, PMID:29186243).
• Consanguinity: irrelevant for FPHH itself (dominant). It is relevant to the allelic recessive KITLG disorders (WS2F, biallelic hypomelanosis–deafness, PMID:35543077).

Protective factors

None reported. No protective allele, dietary factor, or exposure has been described. By mechanistic inference (not evidence), photoprotection would be expected to limit UV-driven darkening superimposed on the constitutive hyperpigmentation, but I found no study testing this in FPHH — curate as inference in notes, not as an evidence-backed claim.

Gene–environment interactions

No published GxE data for FPHH. Two mechanistically plausible but unevidenced axes worth recording as knowledge gaps:

1. UV × KITLG-GOF. SCF/KIT is a keratinocyte-derived paracrine arm of the UV tanning response; a constitutively hyperactive ligand could plausibly exaggerate UV-induced melanogenesis. Untested in FPHH.
2. Somatic second hits. Hida et al. provide the one hard example of a post-zygotic modifier of the phenotype — copy-neutral LOH at the KITLG locus confined to a hypopigmented macule (see §4, §6). That is a genetic–somatic interaction, not environmental.

3. Phenotypes

Core cutaneous phenotype

Quantitative anchors from individual families:

• Lesion size: "the patches (0.2–0.8 cm) progressed successively over her face, neck, trunk and limbs with age," plus "a small number of larger pigmented lesions that were several centimeters in diameter on her trunk and limbs" (PMID:33407466).
• Full-body extent in the index FPH family: "extensive hyperpigmentation of the conjunctive face, neck, trunk, limbs, lips, oral mucosa, palms, and soles" (PMC2680999).
• Morphologic range: "Dispigmentation patterns can range from well-isolated café-au-lait/hypopigmented patches on a background of normal-appearing skin to a confetti-like or mottled appearance" (PMID:33407466).

Extracutaneous features — rare, family-specific, and contested

Two pedigrees carry non-cutaneous findings, and one large series explicitly did not:

• Westerhof family (1978, PMID:666331): 14 affected across 3 generations, Hindustani origin; "Some family members with macules also had retarded growth and mental deficiency." No male-to-male transmission observed. Pre-molecular; KITLG status unknown.
• Chinese 2-year-old girl (IJDVL variant case, cited as ref 11 in PMID:33407466): "mild mental retardation and epilepsy," seizures exceeding 10 hours in the first year, "hyperthermia, frequently over 40 °C," repeated infections, longitudinal melanonychia, reticulate facial pigmentation.
• Counterweight: across the eight KITLG-mutation-positive FPHH families tabulated by Wang J et al., "mental retardation was not present in these FPHH patients"; the recurring extra findings were "Sparse lateral eyebrows and malignancy (pharyngeal cancer, papillary thyroid cancer and melanoma) ... in two families" and "Short sutures ... in only one family" (PMID:33407466).

Curation guidance: treat neurodevelopmental features as unconfirmed and probably not part of the KITLG-defined entity. The two pedigrees reporting them are either pre-molecular or KITLG-untested, and the molecularly confirmed series contradicts them. Record as a KNOWLEDGE_GAP discussion rather than as a phenotype with a frequency.

Malignancy: the three cancers (pharyngeal, papillary thyroid, melanoma) in two families are the only cancer signal, are unreplicated, and are not established as disease-associated. Note that the index FPH family was explicitly cancer-free: "None of the affected members in this family was found to have skin cancer" (PMC2680999). Do not curate FPHH as a cancer-predisposition syndrome.

Quality-of-life impact

No FPHH-specific QoL instrument data exist — no DLQI, EQ-5D, SF-36, or PROMIS study. What the literature supports: the burden is cosmetic and psychosocial, in a highly visible, congenital, progressive, whole-body distribution including the face. One case report is explicit that "The treatment is based solely on cosmetic purposes" (PMID:22577587). There is no documented functional impairment, pain, pruritus, or organ dysfunction. Curate QoL as a knowledge gap with an inferred psychosocial-burden note.

4. Genetic / Molecular Information

Gene

RefSeq accession caution. FPHH papers cite NM_000899.4 / NM_000899.5 (PMID:33407466, PMID:41779177), but Vona et al. cite NM_000889.4 (PMID:35543077) — almost certainly a typographical error for NM_000899.4, since NM_000889 is ITGB7. Do not propagate the Vona accession into the entry.

The variant landscape

All reported FPHH alleles are heterozygous missense substitutions in the KIT-ligand (receptor-binding) domain. There are no truncating, splice, or structural FPHH alleles — consistent with a gain-of-function mechanism where loss-of-function would give a different disease.

Hotspot 1 — exon 2, the "VTNNV" motif, residues 33–37 (extended to VTNNVK, 33–38, by Huang et al.). This β-strand is the third β-strand of KITLG and is directly involved in receptor engagement.

Hotspot 2 — exon 4, the ligand core / third α-helix. Fewer alleles, and phenotypically indistinguishable so far.

Other: p.Ser78Leu — novel, in the Blaschko-linear case (PMID:39269165; cDNA position not given in the abstract — do not invent one).

"Notably, seven known mutations were clustered in a highly conserved short amino acid sequence VTNNV (amino acids 33–37) ... The VTNNV domain of the KITLG protein (amino acids 33–37) lies within the third b-strand of the protein and is responsible for its binding functions." — PMID:33407466

Count discrepancy to flag: Wang J et al. (2021) state eight FPHH alleles; Huang et al. (2024/2026) state "only 10 KITLG mutations reported to cause FPHH" while also writing "seven in nine" are in exon 2. Report the count as approximately 10–12 as of 2026 rather than adopting either figure as exact.

Variant classification and population frequency

• ACMG/AMP evidence applied to c.104A>T and c.101C>T: PS4 (prevalence in affected vs controls), PM1 (mutational hotspot), PP2, PP3; both classified likely pathogenic (PMID:33407466).
• p.Lys38Thr: MutationTaster "disease causing"; "absent in the public databases such as ExAC, dbSNP, and gnomAD"; classified likely pathogenic (PMID:39152874).
• p.Asn36Ser: segregated with disease and "was not detected in 296 healthy unrelated Chinese individuals"; ClinVar RCV000013661 / VCV000379240.
• Wang J et al. additionally sequenced "100 unrelated normal Chinese Han individuals ... to exclude polymorphic variants" — variants absent.

Population frequency: effectively zero. All FPHH alleles are absent or ultra-rare in gnomAD/ExAC/1000 Genomes. I did not retrieve KITLG gene-level constraint metrics (pLI/LOEUF/missense-Z) from gnomAD; a curator wanting them should query gnomAD directly rather than rely on any figure here.

Origin: germline, de novo, and somatic

• Germline, inherited: the majority — multigenerational pedigrees with clean co-segregation.
• De novo: at least three independent cases (p.Lys38Thr, p.Asp110Val, p.Asp110Gly), all confirmed absent in both parents. Sporadic presentation is therefore common enough that a negative family history should not deter testing.
• Somatic mosaicism: a de novo mosaic c.329A>G (p.Asp110Gly) produced "congenital linear and mottled hyperpigmentation" in a 6-year-old boy — i.e. a Blaschko-linear mosaic form of the same allele (cited in PMID:33407466).
• Somatic reversion (the most mechanistically interesting finding in this disease):

"Digital polymerase chain reaction analysis of the DNA from skin and blood tissues indicated a copy-neutral loss of heterozygosity at the KITLG locus, only in the hypopigmented macule. These findings suggest that the hypopigmented macules might result from revertant mosaicism." — Hida et al. 2025, J Dermatol (PMID:39269165)

Functional consequence

Gain of function, established biochemically for p.Asn36Ser and inferred structurally for the rest:

"Function analysis of the soluble form of sKITLG revealed that mutant sKITLG N36S increased the content of the melanin by 109% compared with the wild-type sKITLG in human A375 melanoma cells. Consistent with this result, the tyrosinase activity was significantly increased by mutant sKITLG N36S compared to wild-type control." — PMID:19375057

Absolute values from the full text: "melanin content increased from 16.2 pg per cell (WT sKITLG) to 33.9 pg per cell (mutant sKITLG N36S)"; n=6, two-sided Student's t test (PMC2680999).

Structural rationale for the VTNNV alleles: "Both 35Asn and 34Thr are polar, hydrophilic amino acids, and the mutant became nonpolar, hydrophobic isoleucine; therefore, it might change the features of the protein and affect the ligand affinity to its receptor c-Kit" (PMID:33407466). Note the authors' own hedge: "definitive functional analyses of this mutation are needed."

Important schema note for dismech: per CLAUDE.md's gain/loss decision tree, the variant-level claim belongs in GeneticContext.functional_impact_category: GAIN_OF_FUNCTION; the pathway-activity claim ("melanogenesis driven outside normal keratinocyte-paracrine control") belongs in Descriptor.modifier. Because the KITLG→KIT signal here is genuinely released from its normal regulatory setpoint by a constitutively higher-affinity ligand — not merely running hot — modifier: GAIN_OF_FUNCTION on the KIT-signalling node is defensible; INCREASED on downstream melanin-biosynthesis nodes is the safer, PATO-bound choice. This entry is a legitimate candidate to be the first in the KB to carry both slots on one mutation-driven node.

Allelic disorders (same gene, different mechanism/dose) — essential context

Vona et al.'s dose model is the cleanest statement of the allelic architecture:

"We speculate that KITLG biallelic loss-of-function variants cause generalized hypomelanosis, whilst variants with residual function lead to a variable auditory-pigmentary disorder mostly reminiscent of Waardenburg syndrome type 2 or piebaldism." — PMID:35543077

Note also that heterozygous carriers of a KITLG null "exhibited lighter-coloured skin than expected for their ethnic background" (PMID:35543077) — a direct human dose–response readout on the opposite side of wild-type from FPHH. Together, FPHH (hypermorph) and the null carriers (hypomorph) bracket KITLG as a continuously dose-sensitive determinant of human skin pigmentation. That is the single strongest mechanistic framing for this entry.

Interesting corollary from Huang et al.: the receptor mirrors the ligand — "Mutations in KIT, encoding for the receptor of KITLG, could lead to piebaldism (loss of function in KIT) or skin hyperpigmentation (gain of function in KIT)."

Modifier genes, epigenetics, chromosomal abnormalities

• Modifier genes: none identified. Variable expressivity is unexplained.
• Epigenetics: no DNA-methylation, histone, or chromatin data exist for FPHH. The one 2026 study found transcriptional consequences (MITF) but did not assay epigenome.
• Chromosomal abnormalities: none. FPHH is not a CNV/microdeletion disorder; CMA and karyotype are not indicated (§10). The only large-scale genomic event described is the copy-neutral LOH confined to a hypopigmented macule (PMID:39269165) — a somatic, lesion-restricted event, not a constitutional one.

5. Environmental Information

Not applicable in any causal sense. There are no environmental factors, lifestyle factors, or infectious agents implicated in FPHH. It is fully penetrant-or-not on genotype, congenital in onset, and has no exposure-linked triggers in any published pedigree.

For the environmental: block, the honest curation is either an empty section with a knowledge-gap discussion, or a review_notes: waiver beginning Left deliberately uncited. followed by ≥20 words describing the searches run (PubMed FPHH × exposure; CTD KITLG; ECTO term search for UV/solar radiation exposure) and why nothing citable was found. Do not manufacture a UV-exposure link — it is mechanistically plausible for the tanning arm of KIT signalling but has never been tested in FPHH, and asserting it would fail check-environmental-evidence on substance even if it passed on form.

6. Mechanism / Pathophysiology

The causal chain

Step 1 — Mutant ligand (MOLECULAR). A heterozygous missense substitution in the KIT-ligand domain of KITLG — overwhelmingly in the VTNNVK β-strand (residues 33–38), occasionally in the exon-4 α-helical core (Asp110, Glu113) — alters the receptor-contact surface. Predicted consequence: increased affinity of KITLG for KIT, i.e. a hypermorphic ligand rather than more ligand.

• GO: GO:0005173 stem cell factor receptor binding (verify label); GO:0005125 cytokine activity
• Descriptor: modifier: GAIN_OF_FUNCTION; functional_impact_category: GAIN_OF_FUNCTION

Step 2 — Paracrine over-stimulation of melanocyte KIT (CELLULAR). KITLG is made by the melanocyte's neighbours, not by the melanocyte:

"KITLG, as KIT LIGAND, is produced locally in human skin by epidermal keratinocytes and endothelial cells, where it induces the migration, development and survival of melanocytes." — PMID:33407466

"After KITLG binds the c-KIT receptor, dimerization is triggered. It initiates signal transduction via the RAS/MAPK pathway to upregulate melanoblast proliferation" — PMID:33407466

This is a keratinocyte→melanocyte paracrine axis, which makes FPHH a disease of the melanocyte's niche signal, not of the melanocyte's own genome. Cell types: keratinocyte (CL:0000312) and blood-vessel endothelial cell (CL:0000071) as sources; melanocyte (CL:0000148) and melanoblast (CL:0000541) as targets.

• GO: GO:0038109 Kit signaling pathway (verify); GO:0004714 transmembrane receptor protein tyrosine kinase activity; GO:0007169 cell-surface receptor protein tyrosine kinase signaling pathway

Step 3 — Downstream cascades (CELLULAR). KIT activation feeds RAS–RAF–MAPK, PI3K–AKT, JAK–STAT, and PLCγ1 (GeneCards/UniProt P21583). The FPHH literature emphasizes RAS/MAPK: "KITLG/c-Kit and Ras/MAPK pathways are crucial for controlling pigmentation" (PMID:35543077).

• GO: GO:0000165 MAPK cascade; GO:0014065 phosphatidylinositol 3-kinase signaling

Step 4 — MITF induction (MOLECULAR). MITF is the master melanocyte transcription factor and the convergence point. The 2026 functional study is the first to show transcriptome-wide consequences:

"results showed that the mutation broadly affected the transcription and translation of genes responsible for melanin synthesis, especially the melanin gene MITF." — Wu et al. 2026, Mol Genet Genomics (PMID:41779177)

Step 5 — Tyrosinase up-regulation and increased melanogenesis (CELLULAR). Directly measured: tyrosinase activity and melanin content both rise (§4). Tyrosinase is the rate-limiting enzyme converting L-tyrosine → DOPA → dopaquinone → melanin.

• GO: GO:0042438 melanin biosynthetic process; GO:0004503 monophenol monooxygenase (tyrosinase) activity; GO:0042470 melanosome (CC)
• CHEBI: L-tyrosine (CHEBI:17895, verify); melanin/eumelanin — no confident CHEBI ID; check before binding

Step 6 — Melanin transfer and epidermal deposition (TISSUE). Melanosomes are transferred to basal keratinocytes; histology shows melanin accumulation "throughout the epidermis, especially in the basal cell layer" (PMID:29186243).

• UBERON: skin of body (UBERON:0002097); epidermis (UBERON:0001003); stratum basale — verify ID

Step 7 — Clinical hyperpigmentation, progressive with age (ORGANISM).

The unexplained half: why hypopigmentation?

This is the entry's headline knowledge gap, stated plainly by the field:

"Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH. However, the mechanisms behind hypopigmented macule formation remain unclear." — Hida et al. (PMID:39269165)

Two competing/complementary hypotheses, both worth curating as mechanistic_hypotheses with distinct hypothesis_group_ids:

Hypothesis A — revertant somatic mosaicism (EMERGING, one case). Copy-neutral LOH at the KITLG locus removes the mutant allele in a clone of skin, producing a wild-type (hence relatively hypopigmented) patch on a hyperpigmented background. Supported by: LOH detected by digital PCR "only in the hypopigmented macule," and the lesions following Blaschko lines — the signature of clonal cutaneous mosaicism. Note Amyere et al. also flagged "Loss of Heterozygosity" and "Gene Dosage" as MeSH keywords back in 2011 (PMID:21368769), so the idea has a longer pedigree than the single 2025 report.

Hypothesis B — distinct pathogenesis for CALMs. From the same paper: "café-au-lait spots do not follow the lines of Blaschko and can superimpose on the hypopigmented striae, indicating a distinct pathogenesis." So FPHH skin plausibly carries three superimposed lesion classes with three mechanisms: constitutive diffuse hyperpigmentation (germline GOF), clonal hypopigmented reversion (somatic LOH), and CALMs (mechanism unknown).

Hypothesis C — melanocyte exhaustion/depletion (speculative). Chronic supraphysiological KIT stimulation could plausibly deplete the melanocyte stem-cell pool in patches. No direct evidence. The histology is at least consistent with absence of functioning melanocytes in hypopigmented skin (S100/HMB45 "almost completely negative"), but that cannot distinguish reversion from depletion.

Histopathology — with an explicit conflict to resolve

Hyperpigmented skin:

"Histopathological and immunohistochemical staining for S100 and HMB45 of skin biopsy specimens from the hyperpigmented areas showed a striking increase in melanin throughout the epidermis, especially in the basal cell layer." — PMID:29186243

"strong basilar and suprabasilar hyperpigmentation ... Masson-Fontana stained sections showed an increase in the number of melanocytes in the basal and suprabasal cell layers." — PMID:22577587

Hypopigmented skin:

"The staining for S100 and HMB45 were almost completely negative in the hypopigmentation areas." — PMID:29186243 — i.e. melanocytes are absent, not merely underproductive, which favours Hypothesis A or C over a pure "less melanin per cell" model.

⚠ Conflict — do not paper over this. Wang ZQ et al. 2009 contains an internal contradiction. Its figure caption reports the authors' own biopsy as showing "a significant increase of the number of melanocytes and of the melanin content in the basal keratinocytes, as well as a slight increase in the size of melanocytes," while the main text, citing prior FPH literature, states biopsies showed "increased melanin in the basal layer, but no increase in the number of melanocytes within the epidermis" (PMC2680999). Whether FPHH hyperpigmentation is melanocyte hyperplasia or per-melanocyte hyperfunction is therefore genuinely unsettled — and it matters, because KIT signalling drives both proliferation and melanogenesis. Curate as two evidence items with different supports values, or as a KNOWLEDGE_GAP discussion attached to the melanogenesis node. Do not assert either as fact.

Other mechanism domains

• Protein dysfunction: altered receptor-binding surface, not misfolding or aggregation. SWISS-MODEL 3D modelling shows side-chain changes at Thr34/Asn35 converting polar/hydrophilic to nonpolar/hydrophobic residues (PMID:33407466). No crystal structure of a mutant KITLG–KIT complex has been solved; PDB structures of wild-type SCF/KIT exist and would be the substrate for such work.
• Isoform biology (under-explored, likely important): exon 6 encodes the primary proteolytic cleavage site; NM_000899 (variant b) yields soluble SCF, NM_003994 (variant a) yields membrane-bound SCF. "The soluble form mainly stimulates cellular proliferation; the membrane-bound isoform induces an activation of the receptor more prolonged than the soluble one." Every functional FPHH experiment to date used the soluble form (sKITLG). Whether FPHH alleles differentially affect the two isoforms is unknown and is a good Experiment proposal.
• Metabolic changes: confined to melanin/tyrosine metabolism. No systemic metabolic derangement; "Hematology and blood chemistry did not reveal any abnormalities" (PMID:22577587).
• Immune involvement: none for FPHH. (KITLG is central to mast cell development, CL:0000097, but no mast-cell phenotype has been reported in FPHH patients — a notable negative worth recording.)
• Tissue damage mechanisms: none. FPHH involves no oxidative injury, ischaemia, fibrosis, inflammation, or necrosis. The tissue is structurally normal and abnormally pigmented. This is a dysregulation disease, not a destruction disease — relevant when deciding module conformance (it conforms to no fibrotic/inflammatory/degenerative module in kb/modules/).
• Molecular profiling: transcriptomics only — the 2026 RNA-seq of adenine-base-editor–engineered cells (PMID:41779177). No proteomics, metabolomics, lipidomics, single-cell, spatial, multi-omics, or CRISPR-screen data specific to FPHH. No GEO series exists for FPHH; do not fabricate a datasets: accession — just discover-datasets will surface KITLG-adjacent melanocyte studies that are GENE_ONLY at best and require the manual relevance triage CLAUDE.md warns about.

7. Anatomical Structures Affected

Organ level - Primary: skin (UBERON:0002097) — the only consistently affected organ. Integumentary system. - Secondary: oral mucosa (UBERON:0000344, verify), lips, conjunctiva (UBERON:0001811, verify) — pigmented in some patients, spared in others. - No cardiovascular, neurological, digestive, respiratory, endocrine, renal, or skeletal involvement in molecularly confirmed FPHH. - Allelic-disorder context only: the stria vascularis of the cochlea (UBERON:0002499, verify) is the site of the KITLG hearing phenotype (DFNA69/WS2F), via intermediate cells = cochlear melanocytes. Do not attribute hearing loss to FPHH itself.

Regional distribution: face, neck, trunk, limbs; frequently palms and soles; occasionally sparing them. Distribution is bilateral and broadly symmetric/generalized for the diffuse hyperpigmentation, but the superimposed macules are random and asymmetric, and the reverted hypopigmented lesions follow Blaschko lines (mosaic, not anatomically symmetric).

Tissue level: stratified squamous epithelium of the epidermis (UBERON:0001003); specifically the basal and suprabasal layers. Dermis is uninvolved except as the source of endothelial KITLG.

Cell level | Cell type | CL (verify) | Role | |---|---|---| | Melanocyte | CL:0000148 | Primary effector — hyperfunctional and/or hyperplastic | | Melanoblast | CL:0000541 | Developmental target of KIT signalling | | Keratinocyte | CL:0000312 | Ligand source (paracrine) and melanin recipient | | Basal cell of epidermis | check | Site of melanin accumulation | | Blood-vessel endothelial cell | CL:0000071 | Second dermal ligand source | | Mast cell | CL:0000097 | KIT-dependent lineage; no reported FPHH phenotype (negative finding) |

Subcellular level: melanosome (GO:0042470) — melanin synthesis and transfer; plasma membrane (GO:0005886) — KIT receptor and membrane-bound KITLG; extracellular space (GO:0005615) — soluble sKITLG.

8. Temporal Development

Onset: congenital to early infantile. Multiple independent formulations: - "Generalized hyper- and hypopigmentation with irregular patches was found at birth" (PMID:33407466) - "One week after birth, it was shown that her diffuse hyperpigmented skin was intermixed with some small lentigines/CAL-like lesions" (PMID:33407466) - "present at birth or develop early in infancy" (OMIM #145250 description) - "The pigmentation was present since birth and eventually increased thereafter" (PMID:22577587) - HPO onset category: Congenital onset / Neonatal onset (HP:0003577 / HP:0003623, verify)

Onset pattern: insidious and chronic — never acute, never episodic.

Progression — this is the defining temporal signature and has a documented biphasic rate:

"This process was rapid during childhood and slower during adolescence, and it resulted in extensive hyperpigmentation of the conjunctive face, neck, trunk, limbs, lips, oral mucosa, palms, and soles." — PMC2680999

"With increasing age, the lesions increased in both size and number and became more noticeable" — PMID:33407466

Progression is by three simultaneous axes: individual patches enlarge, new patches appear, and adjacent patches become confluent ("increase in size, number and confluence with age" — Orphanet phrasing for the FPH concept).

Suggested progression: phases for the entry: | Phase | Timing | Description | |---|---|---| | Congenital/neonatal | Birth to ~1 month | Diffuse hyperpigmentation ± large CALM-like patches present or emerging | | Rapid childhood progression | Infancy → ~puberty | Fastest accrual of new lentigines, CALMs, hypopigmented macules; patch enlargement | | Adolescent deceleration | Puberty → early adulthood | Same process, slower rate | | Adult stable/extensive | Adulthood | Extensive, largely stable involvement; a 53-year-old affected male showed no new disease category, and no skin cancer |

Disease course: chronic, lifelong, progressive, non-remitting. No spontaneous remission reported. No relapsing-remitting behaviour. Not self-limited. Life expectancy is unaffected (§11).

Remission: none spontaneous. The only documented local lightening is the somatic-reversion mechanism producing hypopigmented macules (PMID:39269165) — which is a lesion-level genetic event, not clinical remission. Treatment-induced lightening is cosmetic and, by analogy to other benign pigmented lesions, expected to be temporary (§12).

Critical periods: infancy and childhood are the window of maximal lesion accrual, which is when a purely mechanistic argument for early intervention would apply — but no intervention exists to test that, so this is an inference, not a recommendation.

9. Inheritance and Population

Epidemiology

No prevalence or incidence estimate exists in the literature, and the field says so explicitly:

"Because FPHH is very rare with reduced penetrance, no clear incidence rate of this disease has been documented." — PMID:33407466

For the prevalence: block, the correct structured record is:

prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: ULTRA_RARE        # or NOT_YET_DOCUMENTED
  notes: >-
    No incidence or prevalence estimate has been published. Fewer than ~25 molecularly
    confirmed families are reported worldwide as of 2026.

Do not compute a rate_per_100000. A defensible order-of-magnitude anchor for notes: roughly 10–12 distinct KITLG alleles across on the order of 15–20 published families/probands, plus an unknown number of KITLG-negative families — i.e. well under 1 per 1,000,000. Consider fetching ORPHA:280628 for an Orphanet-assigned prevalence class, which would be quotable.

Inheritance

• Autosomal dominant (HP:0000006), consistently across all KITLG-positive pedigrees. Six-generation (PMID:19375057) and four-generation (PMID:33407466) pedigrees with clean co-segregation.
• Penetrance: incomplete/reduced. "FPHH is thought to be an autosomal dominant disorder with reduced penetrance" (PMID:21368769); "a rare autosomal dominant disorder with variable penetrance" (PMID:33407466). No numeric penetrance estimate is available. Note also that the Wang 2009 family showed perfect co-segregation ("cosegregated perfectly with affected, but not with unaffected, members"), so penetrance may be allele-dependent.
• Expressivity: variable — extent of hyperpigmentation, presence/absence of the hypopigmented component, CALM burden, and mucosal involvement all differ within and between families. Huang et al. raise the possibility of allele-specific severity: "Further cases of FPHH caused by the same mutation are warranted to elucidate if the extensive involvement is mutation related."
• Genotype–phenotype correlation: none established. "no clear genotype-phenotype correlations have been established" (PMID:33407466). Exon-2 VTNNVK and exon-4 core alleles are not clinically distinguishable in current data.
• Genetic anticipation: not reported and not expected (missense, not repeat expansion).
• De novo rate: unquantified but clearly non-trivial — ≥3 confirmed de novo probands out of a small published total.
• Germline mosaicism: not reported for FPHH. Somatic mosaicism is documented (the mosaic p.Asp110Gly linear-hyperpigmentation case). Recurrence counselling should nevertheless mention germline mosaicism as a theoretical residual risk for apparently de novo cases.
• Founder effects: none identified. Recurrent alleles (p.Asn36Ser in a Chinese FPH family and two European FPHH families; p.Thr34Ile) are best explained by hotspot recurrence, not shared ancestry — and the trans-continental recurrence of p.Asn36Ser argues directly against a founder.
• Consanguinity: not a factor for FPHH; relevant only to the recessive KITLG disorders.
• Carrier frequency: not applicable (dominant); "carriers" are affected.

Population demographics

• Reported ancestries: Han Chinese (most reports), Japanese, Slovenian, Danish, German, US, Hindustani-origin, Filipino (for the allelic WS2F allele). The Chinese predominance is best read as ascertainment bias — the disease is visually striking, and several large Chinese dermatogenetics groups have driven the field.
• Geographic distribution of variants: exon-2 VTNNVK alleles reported from both East Asia and Europe; exon-4 alleles from Slovenia (p.Asp110Val), Japan (p.Glu113Lys), and China (p.Asp110Gly). No geographic clustering by allele.
• Sex ratio: ~1:1; no sex-limited expression, no skewing. No male-to-male transmission was observed in the Westerhof family, but this is a small-pedigree artefact — male-to-male transmission is present in later pedigrees, excluding X-linkage.
• Age distribution of affected individuals: all ages; the disease is present from birth and persists lifelong. Published patients range from a 2-year-old to a 53-year-old.

10. Diagnostics

Diagnostic approach in one line

FPHH is a clinical diagnosis confirmed by KITLG sequencing, made in an infant or child with congenital diffuse hyperpigmentation plus dyspigmented macules, after NF1/Legius and the dyschromatoses have been considered.

Genetic testing — the definitive test

Variant interpretation: apply ACMG/AMP. Documented codes for FPHH alleles: PS4, PM1 (VTNNVK hotspot), PP1/PP2 (co-segregation), PP3 (in-silico: SIFT "deleterious", PolyPhen-2 "possibly damaging", MutationTaster "disease causing"), PM2 (absent from gnomAD/ExAC/dbSNP). Typical resulting classification: likely pathogenic.

Clinical/laboratory tests

• Routine labs are normal and serve to exclude mimics, not to diagnose. A full endocrine screen in one case — "estimation of serum ACTH, α and β MSH, T3 T4 TSH, and Cortisol levels" — was normal (PMID:22577587). This is the standard workup to exclude Addison disease and ACTH/MSH-driven hyperpigmentation.
• Biomarkers: none. No circulating, imaging, or molecular biomarker for FPHH.
• Imaging: not indicated for FPHH itself. (Indicated only if NF1 remains in the differential.)
• Wood's lamp examination: useful clinically to delineate hypopigmented/ash-leaf macules — standard pigmentary-disorder practice, no FPHH-specific citation.
• Dermoscopy: no published FPHH-specific dermoscopic criteria.
• Audiology: worth considering, not because FPHH causes deafness but because KITLG alleles can, and the DFNA69 phenotype is unilateral or asymmetric and therefore easily missed. Frame as prudent given the gene, and cite the allelic literature (PMID:35543077), never as an FPHH feature.

Biopsy / histopathology

Supportive, not diagnostic. Findings (§6): increased melanin throughout the epidermis, maximal in the basal layer; Masson–Fontana positive; S100 and HMB45 highlight melanocytes in hyperpigmented skin and are "almost completely negative" in hypopigmented areas. Melanocyte number is disputed. No pigmentary incontinence or interface change is characteristic — their presence should redirect to post-inflammatory dyspigmentation or DUH.

Diagnostic criteria and differential diagnosis

There are no formal, society-published diagnostic criteria for FPHH. Diagnosis rests on the clinical triad (congenital/early-infantile onset + diffuse progressive hyperpigmentation + superimposed CALMs/lentigines/hypopigmented macules) + AD family history (when present) + KITLG variant.

Sources for the differential list: PMID:22577587, PMID:39152874, PMID:21368769, IJDVL variant case, and the DUH literature (PMID:37353900).

Screening

• Newborn screening: no. Not screenable, not treatable, no biochemical marker.
• Carrier screening: not applicable (dominant).
• Cascade testing: yes, appropriate — targeted KITLG variant testing of at-risk relatives once a familial variant is known, remembering reduced penetrance.
• Prenatal / PGT: technically feasible once the familial variant is known. Whether it is offered is a values question for a non-lethal, non-progressive-beyond-skin cosmetic condition; that judgement belongs to the family and their genetic counsellor, not to this report.

11. Outcome / Prognosis

Survival and mortality: normal. No FPHH-attributable mortality has ever been reported. No excess mortality, no reduction in life expectancy, no disease-specific mortality rate. Affected individuals survive into at least the sixth decade with no systemic disease (a 53-year-old affected male is described in the index family, PMC2680999). SEER, GBD, CDC, and national mortality databases contain nothing on this disease.

Morbidity and function: no physical disability. No functional impairment, no ICF-codable disability, no organ failure. The burden is cosmetic and psychosocial, in a disorder that is visible, whole-body, facial, congenital, and progressive — but there are no QoL instrument data of any kind (§3). This gap is real and worth recording as such rather than filled with plausible-sounding numbers.

Complications - Cutaneous malignancy: not established. Melanoma occurred in one of two families that also reported pharyngeal and papillary thyroid cancer (PMID:33407466); the index six-generation family had none ("None of the affected members in this family was found to have skin cancer"). Given that KIT-GOF receptor mutations cause GIST, the theoretical concern is not absurd — but the FPHH ligand alleles have no demonstrated neoplastic risk, and a KITLG-GOF melanoma link would be a significant claim requiring far more than one family. Curate as an open question, explicitly not as an established complication. - No infections, no organ failure, no secondary systemic complications.

Recovery potential: none, and none needed. The pigmentary phenotype is permanent; it neither resolves nor threatens health.

Prognostic factors: none identified. No age, severity, biomarker, or genotype predictor of course. Since no genotype–phenotype correlation exists, allele identity currently carries no prognostic information.

Prognostic biomarkers: none.

12. Treatment

Bottom line: there is no disease-modifying therapy, no approved drug, no clinical trial, and no published treatment series for FPHH. Management is cosmetic and supportive. Every statement below is either directly sourced to FPHH literature (little) or drawn from general hyperpigmentation management and labelled as such.

What the FPHH literature actually says

"The treatment is based solely on cosmetic purposes. The cosmetic oral treatment including depigmentation procedure of the gingiva can be carried out." — PMID:22577587 (patient declined; recommended "periodic evaluation")

That is essentially the entirety of the FPHH-specific treatment evidence base.

Supportive / cosmetic management (extrapolated from general dyschromia management — flag as such)

General hyperpigmentation management comprises "photoprotection, topical lightening agents, oral agents, chemical peels, and laser therapy" (PMID:35158001, JAAD review Part II). Applied to FPHH:

Two cautions the curator should keep in the entry, because they are genuine risks rather than boilerplate: 1. Post-inflammatory hyperpigmentation. In skin that is constitutively hypermelanotic under a hyperactive melanogenic drive, any laser or peel carries an elevated PIH risk. The general literature already recommends "broad-spectrum sunscreen with SPF ≥ 30 and physical photoprotection ... after Q-switched laser treatment to prevent post-inflammatory hyperpigmentation" (Tandfonline 2024 RCT). 2. Expected relapse. Ablating melanin does not touch the germline GOF signal.

Targeted therapy — the mechanistically obvious idea, and why it is not a recommendation

The pathway is druggable. Imatinib and other KIT inhibitors reliably cause depigmentation:

Imatinib "inhibits the phosphorylation of c-kit receptor through SCF-induced melanocyte proliferation and melanogenesis"; "even at low concentrations it causes decreases in total melanin content and tyrosinase activity"; "The inhibition of melanogenesis is due to suppressed expression of tyrosinase and microphthalmia-associated transcription factor (MiTF)" (PMID:24479586, and see PMID:14635084)

Depigmentation occurs in 33–41% of imatinib-treated patients (up to ~80% in pigmented populations) and is reversible on withdrawal. Picardo & Cardinali's commentary gestures at exactly this: the KITLG/c-Kit findings "offer hope for the development of new and efficacious treatment strategies" (PMID:21566575).

But: systemic imatinib for a benign cosmetic condition is not a defensible risk–benefit trade, and imatinib also causes hyperpigmentation in some patients (PMC11401049) — the pigmentary response is unpredictable. A topical/intralesional KIT inhibitor would be the rational形 of this idea and does not exist. Curate this as a mechanistic_hypotheses / Experiment proposal or a discussions entry, never as a treatment.

Everything else

• Pharmacogenomics: not applicable — no drug is used.
• Gene therapy, gene editing, cell therapy, RNA therapies (ASO/siRNA), immunotherapy, monoclonal antibodies, surgery, rehabilitation: none applicable, none reported. Note that an allele-selective siRNA/ASO against a dominant GOF ligand is conceptually feasible; nothing has been attempted. Base editing appears in this literature only as a laboratory tool for modelling (PMID:41779177), not as therapy — do not miscurate it as a GENE_EDITING treatment.
• Clinical trials: a ClinicalTrials.gov search for FPHH/KITLG pigmentation yields no interventional trials. Do not populate clinical_trials:.
• Treatment algorithms / combination therapy / personalized medicine: no FPHH-specific pathway exists. The nearest generalizable statement is that "A multimodal approach combining laser therapy and medical treatment may enhance outcomes" for hyperpigmentation broadly.

13. Prevention

Primary prevention of the disease itself is impossible — FPHH is a germline monogenic condition with no environmental component. What is preventable is transmission and procedural harm.

Not applicable: immunization, population screening programmes, newborn screening, behavioural/lifestyle interventions, public-health interventions, environmental interventions, chemoprophylaxis. There is no risk-stratification model.

14. Other Species / Natural Disease

No naturally occurring animal homolog of FPHH exists. OMIA lists no KITLG-GOF hyperpigmentation phenotype in any domestic species, and I found no veterinary report. Curate this section as explicitly empty rather than stretching to fill it.

What does exist is the mirror-image phenotype — Kitl loss of function, which is one of the classic loci of mouse genetics:

• Mouse Kitl — the Steel (Sl) locus (MGI:96974; NCBI Gene 17311; NCBITaxon:10090). "Mouse strains carrying mutations at the Steel (Sl) locus are anemic and display defects in pigmentation and gametogenesis"; "homozygotes of viable mutant alleles have white coats and are sterile and severely anaemic."
• The key insight from Sl vs W (Kit) genetics — directly relevant to FPHH's paracrine mechanism: "the defect in Sl is not intrinsic to the progenitor stem cells of the affected tissues, but rather lies in the environment in which melanoblast, germ cell, and hematopoietic progenitors differentiate and proliferate." FPHH is the same architecture with the sign reversed: a niche-derived signal that is too strong.
• Sl mutations "exert deleterious effects on three migratory cell lineages (primordial germ cells, melanocytes and hematopoietic stem cells) resulting in loss of pigmentation, reduced fertility and anemia."
• Human relevance of the dose axis: "Mutant alleles of the KITLG gene are lethal in homozygous mice and produce a variable level of coat-color dilution in heterozygous mice" (PMID:33407466) — which matches the human observation that heterozygous KITLG-null carriers have lighter-than-expected skin.

Orthologs: Kitl (mouse, MGI:96974), Kitlg (rat), kitlga/kitlgb (zebrafish — the duplicated teleost paralogs; kitlga governs melanophore development), plus conserved orthologs across vertebrates. The KITLG–KIT axis is deeply evolutionarily conserved as the core melanocyte-development module across vertebrates, which is why the mouse and zebrafish literatures translate well.

Comparative pathology: the loss-of-function side translates cleanly (mouse Sl/W, human piebaldism/WS2, dog/horse/pig KIT white-spotting alleles). The gain-of-function side — FPHH's actual mechanism — has no natural animal counterpart, which is precisely why the engineered models in §15 matter.

Zoonosis / cross-species transmission: not applicable.

15. Model Organisms

The honest headline

There is no animal model carrying a human FPHH allele. No knock-in mouse expressing p.Asn36Ser, p.Thr34Ile, p.Asp110Val, or any other FPHH variant has been reported. Everything below either models the pathway in the right direction (K14-Scf), models the gene in the wrong direction (Kitl LOF), or models the variant in cells rather than an organism. This should be curated as an explicit HUMAN_MODEL_MISMATCH discussion, not as a routine KNOWLEDGE_GAP: model evidence exists and is informative for the pathway, but no model reproduces the human FPHH mechanism.

Available systems

1. K14-Scf (K14-Kitl) transgenic mouse — the closest functional analog of FPHH. Krt14 promoter drives SCF in basal keratinocytes; this is a gain of keratinocyte-derived KITLG signal, the same directional perturbation as FPHH.

• Phenotype: "constitutive expression of SCF by epidermal keratinocytes results in retention of melanocytes in the interfollicular basal layer and pigmentation of the epidermis itself"; "Forced expression of SCF in K14-Scf transgenic mice promotes proliferation, differentiation, and migration of melanoblasts during embryogenesis as well as melanocyte stem cells during hair cycling, resulting in a larger number of epidermal melanocytes and epidermal hyperpigmentation."
• Why it matters for §6's unresolved question: this model produces hyperpigmentation via increased epidermal melanocyte number. That is direct model-organism support for the "melanocyte hyperplasia" side of the disputed FPHH histology.
• Fidelity: MODERATE. Right pathway, right direction, right cell-cell axis, right tissue outcome. Limitations: transgenic overexpression of wild-type SCF at supraphysiological levels driven by a heterologous promoter — not a heterozygous, endogenously regulated, affinity-altered ligand. It also fixes the ligand level rather than the ligand quality, so it cannot address the affinity hypothesis at all. And it is fundamentally a humanizing model (normal mouse epidermis lacks interfollicular melanocytes), meaning it corrects a species difference rather than reproducing a disease.
• Suggested link: relationship: PARTIALLY_RECAPITULATES, fidelity: MODERATE, readouts = epidermal melanocyte count (INCREASED), epidermal melanin content (INCREASED).

2. Kitlg^Δ/+ frameshift mouse (2025) — the LOF counterpart. Xiao et al., Genes & Diseases 2025; PMID:41584853, DOI 10.1016/j.gendis.2025.101890 (PMC12824913). CRISPR/Cas9 heterozygous Kitlg c.81_84del, p.E27DfsX5.

• Phenotype: "Abnormal hair coloration (white hair on belly/forehead) in most mutant mice"; "Some Kitlg^Δ/+ mice displayed unilateral or asymmetric hearing loss; others retained normal hearing."
• Mechanism: "reduced KITLG expression impairs melanin synthesis in the stria vascularis without affecting intermediate cell migration"; proposes "a dual-hit model" with compensatory cAMP activation explaining incomplete penetrance.
• Fidelity for FPHH: this model is FAILS_TO_RECAPITULATE FPHH — it is a haploinsufficiency model producing hypopigmentation and deafness (DFNA69/WS2F), the opposite phenotype. Its value to an FPHH entry is (a) confirming KITLG dose-sensitivity of pigmentation in vivo, and (b) modelling the incomplete penetrance that FPHH also shows. If curated, it must carry limitations and its own evidence per test_failure_to_recapitulate_links_are_substantiated.

3. Steel (Sl) allelic series — the historical LOF resource (MGI:96974); dozens of alleles from null (homozygous lethal) to hypomorphic (viable, white-coated, sterile, anaemic). Same directional caveat as above.

4. Cell models — where the actual FPHH variants have been tested. - A375 human melanoma cells + recombinant soluble sKITLG (WT vs N36S). Readouts: melanin content 16.2 → 33.9 pg/cell; tyrosinase activity significantly increased; n=6, two-sided t-test (PMID:19375057, PMC2680999). evidence_source: IN_VITRO. Limitation worth stating in the entry: A375 is a melanoma line, not a normal melanocyte, and the assay adds exogenous soluble ligand rather than modelling heterozygous endogenous expression in a keratinocyte–melanocyte co-culture. - Adenine base editor–engineered cells + RNA-seq (2026). The first modern functional platform for FPHH: "Functional changes were explored at a cellular level with the help of adenine base editors, and the differentially expressed genes in the melanin pathway were detected through RNA-sequencing" (PMID:41779177). This is the model system to build on — it edits the endogenous locus rather than adding recombinant protein. - Human explanted skin (historical, cited in PMID:33407466): "Injection of the soluble form of sKITLG resulted in hyperpigmentation of the grafted skin tissue, while injection of the KIT- or KITLG-blocking antibodies into the explanted human skin led to a loss of melanocytes." A human-tissue bidirectional demonstration of the axis — the highest-fidelity evidence available and a strong candidate for an experimental_models: entry with modeled_mechanisms. - In silico: SIFT, PolyPhen-2, MutationTaster, SWISS-MODEL homology modelling (PMID:33407466, PMID:39152874). evidence_source: COMPUTATIONAL.

5. Not yet used but obvious: zebrafish kitlga (melanophore patterning, live imaging, high throughput); human iPSC-derived melanocytes; keratinocyte–melanocyte co-culture or 3D reconstructed skin with an FPHH allele knocked into the keratinocyte compartment — which is the only system that would test the paracrine architecture properly. None reported.

Proposed experiments worth curating

1. Knock-in mouse carrying an FPHH allele (p.Asn36Ser or p.Asp110Val) at endogenous Kitl. would_support: pathophysiology#KITLG Gain-of-Function Signaling. supporting_outcome: progressive epidermal hyperpigmentation with age; increased epidermal melanocyte number and/or melanin per cell.
2. Direct binding kinetics (SPR/BLI) of mutant vs WT KITLG against KIT ectodomain. This tests the field's central unproven assumption — every "increased affinity" statement in the literature is inference from structure, never measured. would_refute if Kd is unchanged.
3. Isoform-resolved functional assay — soluble vs membrane-bound mutant KITLG, since all existing data used the soluble form only.
4. Lesion-level genomics across a patient's skin — digital PCR / low-pass WGS on paired hyper-, hypo-, CALM, and normal-appearing skin, to test whether the revertant-mosaicism finding (PMID:39269165) generalizes beyond one patient and whether CALMs carry a separate somatic event.
5. Topical KIT inhibition in the K14-Scf mouse, as proof of concept for a non-systemic targeted approach.

Resources

MGI (Kitl MGI:96974, Steel allele series, IMSR strain availability), IMPC/KOMP, Alliance of Genome Resources, ZFIN (kitlga), Cellosaurus/ATCC (A375, CVCL_0132), Addgene (ABE constructs).

Summary of gaps to curate as discussions

Sources

• Wang ZQ et al. 2009, Am J Hum Genet — PMID:19375057 · PMC2680999 full text
• Amyere M et al. 2011, J Invest Dermatol — PMID:21368769 · JID full text
• Picardo M & Cardinali G 2011, J Invest Dermatol — PMID:21566575
• Zeng L et al. 2016, Clin Exp Dermatol — PMID:27859606
• Chinese FPHH family, genetic heterogeneity — PMID:29186243, An Bras Dermatol (SciELO)
• Kato M et al. 2020, J Dermatol — PMID:32189379
• Wang J et al. 2021, BMC Med Genomics — PMID:33407466 · PMC7789533
• Gorenjak M et al. 2021, Mol Genet Genomic Med — PMID:34716665
• Vona B et al. 2022, J Eur Acad Dermatol Venereol — PMID:35543077
• Xu Z et al. 2022, Zhonghua Yi Xue Yi Chuan Xue Za Zhi — PMID:36453959
• Huang X et al., Indian J Dermatol Venereol Leprol — PMID:39152874
• Hida T et al. 2025, J Dermatol — PMID:39269165
• Wu B et al. 2026, Mol Genet Genomics — PMID:41779177
• Xiao Y et al. 2025, Genes & Diseases (Kitlg mouse) — PMC12824913
• Westerhof W et al. 1978, Arch Dermatol — PMID:666331
• FPH oral case report — PMID:22577587 / PMC3337584
• Familial progressive hypo- and hyperpigmentation: a variant case, IJDVL
• OMIM #145250 FPHH · OMIM #614233 FPH1 · OMIM *184745 KITLG · OMIM #616697 DFNA69 · OMIM #619947 WS2F
• GTR condition C1840392 · ClinVar VCV000379240
• Genomics England PanelApp — KITLG, Pigmentary skin disorders
• Orphanet ORPHA:79146 · ORPHA:280628
• MalaCards — FPHH · GeneCards KITLG · MGI Kitl MGI:96974
• Zhou et al. 2023, DUH retyping — PMID:37353900 · OMIM #127500 DUH1 · OMIM 612715 DUH2
• Disorders of hyperpigmentation Part II, JAAD — PMID:35158001 · Q-switched laser retrospective — PMC8544362 · Post-QS-laser PIH RCT 2024
• Imatinib inhibits human epidermal melanocytes — PMID:24479586 · Imatinib causes skin hypopigmentation — PMID:14635084 · Imatinib-induced hyperpigmentation — PMC11401049
• K14-Scf model context, Cell Reports · SCF rescues pigmentation in albino mice — PMID:19682281
• KITLG rs995030 / TGCT — OMIM #273300 · SHEP7 OMIM #611664

Suggested next step: before drafting the YAML, run just structured-rebuild-orphanet --id 280628 --id 79146 (needs the Orphadata bulk XML) to get quotable ORPHA: rows for the prevalence class, HPO frequency table, and gene-disease assertion — that would convert three of the qualitative gaps above (prevalence, phenotype frequencies, gene-disease validity) into snippet-validated evidence. Want me to attempt that, or go straight to expanding the stub's pathophysiology and phenotypes blocks from what is already in references_cache/?

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

• PMID:19375057 (abstract only): "To our knowledge, these data provided the first genetic evidence that the FPH disease is caused by the KITLG N36S mutation, which has a gain-of-function effect on the melanin synthesis"
• closest text in source: "To our knowledge, these data provided the first genetic evidence that the FPH disease is caused by the KITLGN36S mutation, which has a gain-of-function effect on the melanin synthesis and opens a new avenue for exploration of the genetic mechanism of FPH."
• PMID:29186243 (abstract only): "Familial progressive hyperpigmentation and hypopigmentation without KITLG mutation"
• closest text in source: "BACKGROUND: Familial progressive hyper- and hypopigmentation (FPHH) is a rare genodermatosis that is characterized by diffuse hyper- and hypopigmented spots on the skin and mucous membranes"
• PMC:PMC2680999 (abstract only): "extensive hyperpigmentation of the conjunctive face, neck, trunk, limbs, lips, oral mucosa, palms, and soles"
• closest text in source: "Familial progressive hyperpigmentation (FPH) is an autosomal-dominantly inherited disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age"
• PMC:PMC2680999 (abstract only): "None of the affected members in this family was found to have skin cancer"
• closest text in source: "This mutant "G" allele cosegregated perfectly with affected, but not with unaffected, members of the FPH family"
• PMID:22577587 (abstract only): "The treatment is based solely on cosmetic purposes"
• Text part not found as substring: 'The treatment is based solely on cosmetic purposes' (note: only abstract available for PMID:22577587, full text may contain this excerpt)
• PMID:19375057 (abstract only): "Function analysis of the soluble form of sKITLG revealed that mutant sKITLG N36S increased the content of the melanin by 109% compared with the wild-type sKITLG in human A375 melanoma cells. Consistent with this result, the tyrosinase activity was significantly increased by mutant sKITLG N36S compared to wild-type control."
• closest text in source: "Function analysis of the soluble form of sKITLG revealed that mutant sKITLGN36S increased the content of the melanin by 109% compared with the wild-type sKITLG in human A375 melanoma cells"
• PMID:22577587 (abstract only): "strong basilar and suprabasilar hyperpigmentation ... Masson-Fontana stained sections showed an increase in the number of melanocytes in the basal and suprabasal cell layers."
• closest text in source: "Familial progressive hyperpigmentation (FPH) is a rare genodermatosis characterized by hyperpigmented patches in the skin and mucous membranes, present in early infancy, and increase in size and number with age"
• PMID:29186243 (abstract only): "The staining for S100 and HMB45 were almost completely negative in the hypopigmentation areas."
• closest text in source: "Histopathological and immunohistochemical staining for S100 and HMB45 of skin biopsy specimens from the hyperpigmented areas showed a striking increase in melanin throughout the epidermis, especially in the basal cell layer, and staining of hypopigmented area specimens displayed lower levels of melanin in the epidermis"
• PMC:PMC2680999 (abstract only): "increased melanin in the basal layer, but no increase in the number of melanocytes within the epidermis"
• closest text in source: "Function analysis of the soluble form of sKITLG revealed that mutant sKITLGN36S increased the content of the melanin by 109% compared with the wild-type sKITLG in human A375 melanoma cells"
• PMID:22577587 (abstract only): "Hematology and blood chemistry did not reveal any abnormalities"
• Text part not found as substring: 'Hematology and blood chemistry did not reveal any abnormalities' (note: only abstract available for PMID:22577587, full text may contain this excerpt)
• PMID:22577587 (abstract only): "The pigmentation was present since birth and eventually increased thereafter"
• closest text in source: "Familial progressive hyperpigmentation (FPH) is a rare genodermatosis characterized by hyperpigmented patches in the skin and mucous membranes, present in early infancy, and increase in size and number with age"
• PMC:PMC2680999 (abstract only): "This process was rapid during childhood and slower during adolescence, and it resulted in extensive hyperpigmentation of the conjunctive face, neck, trunk, limbs, lips, oral mucosa, palms, and soles."
• closest text in source: "Familial progressive hyperpigmentation (FPH) is an autosomal-dominantly inherited disorder characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age"
• PMID:22577587 (abstract only): "The treatment is based solely on cosmetic purposes. The cosmetic oral treatment including depigmentation procedure of the gingiva can be carried out."
• closest text in source: "Our paper stresses the need for the dentist to be aware of the systemic conditions that can also manifest in the oral cavity."
• PMID:24479586 (abstract only): "The inhibition of melanogenesis is due to suppressed expression of tyrosinase and microphthalmia-associated transcription factor (MiTF)"
• closest text in source: "This inhibition of melanogenesis was due to suppressed expression of tyrosinase and microphthalmia-associated transcription factor (MiTF)"
• PMID:14635084 (abstract only): "The inhibition of melanogenesis is due to suppressed expression of tyrosinase and microphthalmia-associated transcription factor (MiTF)"
• closest text in source: "Microphthalmia (Mi), a basic helix-loop-helix leucine zipper (bHLHZip) transcription factor, is phosphorylated by MAP kinase at a serine residue (S73)"

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMC:PMC8544362 (3 mentions) - Nanosecond Q-Switched 1064/532 nm Laser to Treat Hyperpigmentations: A Double Center Retrospective Study.
• shared terms: hyperpigmentation

Weighed against this report's own most characteristic terms: fphh, kitlg, hyperpigmentation, skin, disease, allele, gene, kit, variant, family, hypopigmented, macule, melanocyte, cell, progressive, affected, genetic, phenotype, congenital, disorder.

Quotes that could not be checked

There was no text to compare these against, so they are neither confirmed nor contradicted:

• DOI:10.1080/09546634.2024.2398768: "broad-spectrum sunscreen with SPF ≥ 30 and physical photoprotection ... after Q-switched laser treatment to prevent post-inflammatory hyperpigmentation"
• Reference resolved but exposes no abstract or full text to search

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

• NCIT:C15747 (3 mentions) - the report calls it "Direct cosmetic benefit, zero risk", "Visible congenital difference"; NCIT calls it Supportive Care

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

• GO:0014065 (obsolete phosphatidylinositol 3-kinase signaling) (1 mention) - replaced by GO:0043491
• GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• NCIT:C15747 - called "Direct cosmetic benefit, zero risk", "Visible congenital difference"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.