Familial Progressive Hyperpigmentation With Or Without Hypopigmentation

Mendelian MONDO:0007771 Pathograph 13 Show in embeddings browser Skin Disorder Genodermatosis

KITLG is the ligand for KIT, and keratinocytes secrete it at melanocytes sitting in the same epidermis. The disease-causing variants do not break that signal; they strengthen it. Almost all of them fall in a five-residue stretch of exon 2 - the conserved VTNNV motif at amino acids 33-37 - which is the surface KITLG presents to its receptor. Exactly how a substitution there strengthens the signal is inferred rather than measured: homology modelling suggests it raises the ligand's affinity for KIT, and no binding or receptor-activation assay on a mutant ligand has been published. What has been measured is the output. Adding the mutant soluble ligand to cells raises tyrosinase activity and roughly doubles melanin content, and a base-edited model shows the melanogenic transcriptional program, MITF included, shifting with it. Clinically that is diffuse hyperpigmentation present at or shortly after birth and spreading with age. The name carries the disease's central awkwardness. Some families have hyperpigmentation and nothing else; others have the same progressive brown background scattered with cafe-au-lait macules, lentigines, and pale macules. These were described under separate labels - FPH and FPHH - and within KITLG the labels do not track distinct lesions: Amyere and colleagues found the p.Asn36Ser allele originally reported in an FPH family segregating in two FPHH families, and mapped the whole set to the same 12q interval that dyschromatosis universalis hereditaria 2 maps to. Presence or absence of the hypopigmented component is therefore treated here as variability within one entity. What that argument does not cover is FPH1, which is a different disease with a confusingly similar name. A three-generation Chinese family with hyperpigmentation only was mapped to 19p13.1-pter, nowhere near KITLG, and its gene is still unidentified. So "familial progressive hyperpigmentation" names two things: a phenotype label used loosely across the KITLG literature, and a specific unsolved 19p locus. Only the first is folded into this entry. The pale macules are the part that is genuinely not understood, and the most interesting recent finding is that they may not be a pigmentary defect at all. In a patient whose hypopigmented macules and streaks followed the lines of Blaschko, digital PCR on lesional skin found copy-neutral loss of heterozygosity at the KITLG locus present in the pale skin and absent from blood - that is, clones that had lost the mutant allele and reverted to normal pigmentation, looking pale only against an abnormally dark background. If that generalises, "hypopigmentation" in this disease is a misnomer for patches of unaffected skin. It is a single patient, and the cafe-au-lait macules in the same person did not follow Blaschko lines and so need a different explanation.

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Inheritance
7
Pathophys.
1
Histopath.
6
Phenotypes
5
Gaps
13
Pathograph
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Genes
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Medical Actions
5
Differentials
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Models
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Deep Research
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Inheritance

1
Autosomal dominant HP:0000006
Heterozygous KITLG variants segregate with the phenotype through multi-generation pedigrees; the founding report followed a six-generation Chinese family. Penetrance has been described as reduced, and de novo cases occur - one exon-4 variant was shown to be de novo, and a sporadic patient with unaffected parents has been reported carrying the recurrent p.Thr34Ile allele.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:19375057 SUPPORT Human Clinical
"This mutant "G" allele cosegregated perfectly with affected, but not with unaffected, members of the FPH family."
Cosegregation of the heterozygous KITLG allele with affected status across a six-generation pedigree, which is the dominant-inheritance evidence.
PMID:21368769 SUPPORT Human Clinical
"Familial progressive hyper- and hypopigmentation (FPHH) is thought to be an autosomal dominant disorder with reduced penetrance."
States the dominant mode and flags reduced penetrance; graded PARTIAL because the sentence reports the prevailing view rather than a penetrance measurement.
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Discussions and Knowledge Gaps

5
Do the hypopigmented macules of FPHH represent a pigmentary defect, or are they revertant clones that have lost the mutant KITLG allele and simply look pale against hyperpigmented skin?
KNOWLEDGE GAP fphh_hypopigmentation_reversion
Attached to
pathophysiology#Somatic Reversion of the KITLG Locus in Skin phenotypes#Hypopigmented Macules and Streaks
The answer changes what the disease is. If the pale lesions are revertant clones, the "with or without hypopigmentation" in the disease name describes a secondary somatic phenomenon rather than a second primary lesion, and the FPH/FPHH split collapses further - FPHH would be FPH plus reversion events. The single supporting observation is lesion-restricted copy-neutral loss of heterozygosity in Blaschko-linear striae in one patient, and the same paper notes that the cafe-au-lait macules do not follow Blaschko lines, so reversion cannot be the whole account of the dyspigmentation.
Proposed experiments
Lesion-restricted allele-ratio testing across an FPHH cohort
fphh_lesional_allele_ratio
Digital PCR or deep amplicon sequencing of the causal KITLG allele in matched hypopigmented lesional skin, adjacent hyperpigmented skin, and blood from multiple unrelated FPHH patients carrying different alleles, to establish whether copy-neutral LOH in pale lesions is general or was a single-patient finding.
Would support
pathophysiology#Somatic Reversion of the KITLG Locus in Skin
Would refute
pathophysiology#Somatic Reversion of the KITLG Locus in Skin
Supporting outcome
  • Loss of the mutant allele restricted to hypopigmented lesional skin in a substantial fraction of patients, absent from adjacent hyperpigmented skin and from blood.
Refuting outcome
  • Mutant allele retained at germline ratio in hypopigmented lesions across the cohort, indicating the pale macules arise by a mechanism other than reversion.
What accounts for FPHH in the families in which no KITLG variant is found?
KNOWLEDGE GAP fphh_kitlg_negative_locus_heterogeneity
Attached to
genetic#KITLG
Locus heterogeneity is documented but no second gene has been identified. Since KITLG acts through KIT and the melanogenic transcriptional program it drives, variants elsewhere on that axis are the obvious candidates, but this has not been shown. Practically, it means a negative KITLG test cannot exclude the diagnosis.
Proposed experiments
Exome or genome sequencing of KITLG-negative FPHH pedigrees
fphh_kitlg_negative_exome
Unbiased sequencing of multiplex families meeting FPHH clinical criteria in whom KITLG coding sequence is normal, with attention to KIT and to MITF-pathway melanogenic regulators.
Would support
pathophysiology#Enhanced KITLG-KIT Signaling in Epidermal Melanocytes
Supporting outcome
  • Identification of segregating variants in a second gene on the KITLG-KIT-MITF axis, which would confirm the pathway while establishing the disorder as genetically heterogeneous.
Is the hyperpigmentation of FPHH caused by more melanocytes, or by the same number of melanocytes each making more pigment?
KNOWLEDGE GAP fphh_hyperplasia_vs_hyperfunction
Attached to
pathophysiology#Increased Melanocyte Melanin Content histopathology#Increased epidermal melanin, maximal in the basal layer animal_models#Mouse
The two lines of evidence in this entry point different ways, and the entry commits to one of them in its pathograph, so the disagreement should be visible rather than buried. The functional work measures output per cell: adding mutant soluble ligand to a melanoma line raised tyrosinase activity and roughly doubled melanin content, with no claim about cell number. That is hyperfunction, and it is what the pathograph models. The immunohistochemistry points the other way: S100 and HMB45 staining of hyperpigmented skin was read as showing increased melanocytes as well as increased melanin. KITLG-KIT signalling is known to drive melanocyte proliferation as well as pigment production, so a gain-of-function ligand could plausibly do both, and the two readings are not mutually exclusive. A third line points the same way as the histology. Targeting KITLG expression to keratinocytes in mice produces epidermal melanocytosis - more melanocytes in the interfollicular epidermis - alongside the increased pigment, so an excess keratinocyte signal demonstrably can expand the population rather than only drive it harder. Neither observation settles it. The functional experiment used exogenous ligand on a cell line and could not have detected a proliferative effect in skin. The histology came from a family in which no KITLG mutation was found, so it may not describe this entity's mechanism at all. The mouse overexpresses wild-type ligand and starts from an epidermis that normally has no interfollicular melanocytes at all. What is missing is a melanocyte count in genotyped patient skin.
Proposed experiments
Melanocyte density in genotyped FPHH skin
fphh_melanocyte_density
Quantitative melanocyte counts, by melanocyte-specific immunohistochemistry on standardised biopsy fields, comparing lesional hyperpigmented skin against non-lesional skin from the same patient and against matched controls, in patients with a confirmed KITLG variant.
Would support
pathophysiology#Increased Melanocyte Melanin Content
Would refute
pathophysiology#Increased Melanocyte Melanin Content
Supporting outcome
  • Melanocyte density in lesional skin indistinguishable from non-lesional and control skin, leaving increased melanin per cell as the explanation and confirming the pathograph as modelled.
Refuting outcome
  • Melanocyte density significantly raised in lesional skin, indicating the pigment excess is at least partly a proliferative effect and requiring a melanocyte-proliferation node the pathograph does not currently have.
Is FPHH strictly skin-limited, or do the extracutaneous features reported in some pedigrees belong to the KITLG disease?
KNOWLEDGE GAP fphh_extracutaneous_involvement
Attached to
phenotypes#Progressive Diffuse Hyperpigmentation genetic#KITLG
This entry curates no systemic phenotype, and that is a decision rather than a finding. On one side, an affected pedigree was explicitly reported to have no other skin, nail, hair, teeth, mucosal, or systemic disease. On the other, the same review's survey of reported families records sparse lateral eyebrows and malignancy in two families and short sutures in one, and older pre-molecular reports under the "melanosis universalis hereditaria" label describe growth and developmental abnormalities. The negative comes from a single pedigree and cannot carry a disease-level claim; the positives are mostly from families that were never genotyped, in an era when the label was applied loosely and when what is now known to be a separate 19p disease was not distinguishable. Until genotyped series report systematically on extracutaneous findings, neither "skin-limited" nor "syndromic" is supportable, so the entry asserts neither.
Show evidence (2 references)
PMID:33407466 SUPPORT Human Clinical
"All the affected individuals in this family had similar lesions, and none of them showed any other skin, nail, hair, teeth, mucosal or systemic diseases."
The skin-limited observation. Graded PARTIAL because it is scoped to one family by its own wording and cannot establish a disease-level negative.
PMID:33407466 SUPPORT Human Clinical
"Sparse lateral eyebrows and malignancy (pharyngeal cancer, papillary thyroid cancer and melanoma) were found in two families. Short sutures were found in only one family, and mental retardation was not present in these FPHH patients"
The contrary observations from the same survey, including its own negative on intellectual disability - which is what the older syndromic reports had claimed.
Do KITLG gain-of-function alleles carry any increased risk of melanoma or other malignancy, or is the reported cancer an artefact of small numbers?
KNOWLEDGE GAP fphh_malignancy_risk
Attached to
genetic#KITLG clinical_burden#
Malignancy - pharyngeal cancer, papillary thyroid cancer, and melanoma - was noted in two of the reported FPHH families, while the six-generation index family had none. Gain-of-function mutations in KIT, the receptor this ligand activates, cause gastrointestinal stromal tumour, so a neoplastic effect of chronic pathway activation is not implausible on its face. But the total reported literature is a few dozen patients, cancers of these types occur in unselected families, and no age-adjusted comparison has been made. This is recorded as an open question specifically so that it is not curated as an established complication, which would put surveillance recommendations on a single uncontrolled observation.
Proposed experiments
Age-adjusted cancer incidence in an assembled KITLG-variant cohort
fphh_cancer_incidence_cohort
Pool molecularly confirmed KITLG gain-of-function carriers across reporting centres and compare observed cancer incidence, melanoma in particular, against population rates matched for age, sex, and ancestry.
Supporting outcome
  • Cancer incidence significantly above matched population rates in variant carriers, which would make surveillance a live question.
Refuting outcome
  • Incidence indistinguishable from population rates, establishing the reported cancers as coincidental and closing the question.
Show evidence (1 reference)
PMID:33407466 SUPPORT Human Clinical
"Sparse lateral eyebrows and malignancy (pharyngeal cancer, papillary thyroid cancer and melanoma) were found in two families."
The observation that raises the question. Graded PARTIAL because it is an uncontrolled tally across two reported families with no denominator or population comparison, so it supports opening the question rather than an association.
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Pathophysiology

7
KITLG Gain-of-Function Variant in the Receptor-Binding Motif
A heterozygous missense substitution in KITLG, almost always within the conserved VTNNV motif spanning amino acids 33-37 in exon 2. The motif lies on a conserved beta-strand that forms the interface with the KIT receptor, so a substitution there alters the ligand-receptor contact rather than destabilising the protein. Reported alleles include p.Val33Ala, p.Thr34Pro, p.Thr34Ile, p.Asn35Ile, p.Asn35Lys, p.Asn36Ser, and p.Lys38Thr - the last extending the hotspot by one residue, so it is sometimes written VTNNVK, 33-38. Alleles outside the motif are also reported: p.Glu113Lys (c.337G>A, exon 4), described as lying at a different ligand-receptor interaction site; p.Ser78Leu, reported as novel with no stated structural interpretation; and a pair of exon-4 substitutions at c.329A.
keratinocyte CL:0000312 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves keratinocyte (CL:0000312). CL:0000312 is a cell type from the Cell Ontology.
Genetic context KITLG hgnc:6343 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KITLG (hgnc:6343). hgnc:6343 is a gene from the HUGO Gene Nomenclature Committee. allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION
stem cell factor receptor binding GO:0005173 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased stem cell factor receptor binding (GO:0005173). GO:0005173 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Enhanced KITLG-KIT Signaling in Epidermal Melanocytes
Somatic Reversion of the KITLG Locus in Skin Reversion is loss of this germline allele in a somatic clone, so the variant is what the reversion event acts on. The intermediates - what triggers mitotic recombination at this locus, and why it appears to happen often enough to be visible - are unknown.
Show evidence (4 references)
PMID:19375057 SUPPORT Human Clinical
"Mutation profiling of positional candidate genes detected a heterozygous transversion (c. 107A-->G) in exon 2 of the KIT ligand (KITLG) gene, predicted to result in the substitution of a serine residue for an asparagine residue at codon 36 (p.N-->S)."
The founding variant, identified by positional cloning after linkage to 12q21.31-q23.1.
PMID:33407466 SUPPORT Human Clinical
"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."
Locates the mutational hotspot. Note the source's own hedging - the affinity increase is offered as what a mutated motif "may" do, on the basis of homology modelling, not as a measured binding result.
PMID:21368769 SUPPORT Human Clinical
"All three mutations were located in a conserved β-strand in KITLG, suggesting its important role in the activation of the KITLG receptor c-Kit."
Independent confirmation that the FPHH alleles cluster on the conserved receptor-contact beta-strand.
+ 1 more reference
Enhanced KITLG-KIT Signaling in Epidermal Melanocytes
Keratinocyte-derived KITLG binds KIT on neighbouring epidermal melanocytes, dimerising the receptor and activating its tyrosine kinase. That this axis is rate-limiting for epidermal pigment is well supported: adding soluble KITLG to grafted human skin darkens it, and blocking either KITLG or KIT depletes melanocytes. What is not established is the step this node names. The proposal is that the mutant ligand engages KIT more effectively than wild type, and the sources state it as a possibility rather than a finding - the affinity increase is inferred from homology modelling of the substituted residues, and no binding assay, receptor phosphorylation measurement, or dose-response comparison of mutant against wild-type ligand has been published. Every functional experiment in this literature reads out melanin or transcription downstream, not receptor engagement itself. The node is graded PROVISIONAL for that reason, and the evidence attached below characterises the wild-type axis rather than the mutant's behaviour on it.
epidermal melanocyte CL:2000000 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal melanocyte (CL:2000000). CL:2000000 is a cell type from the Cell Ontology.
Kit signaling pathway GO:0038109 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Kit signaling pathway (GO:0038109). GO:0038109 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Upregulated MITF-Driven Melanogenic Transcription
Show evidence (4 references)
PMID:39269165 SUPPORT Human Clinical
"KITLG, expressed by keratinocytes, binds to KIT on melanocytes, stimulating melanogenesis. Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH."
States the cell-to-cell signalling axis and attributes the diffuse hyperpigmentation to its disturbance.
PMID:33407466 SUPPORT Human Clinical
"By KITLG binding, KIT dimerizes and initiates diverse cellular responses and plays a crucial role in the development and maintenance of the melanocyte lineage in adult skin."
The receptor-activation step and its role in maintaining the adult epidermal melanocyte lineage.
PMID:33407466 SUPPORT Model Organism
"Injection of the soluble form of sKITLG resulted in hyperpigmentation of the grafted skin tissue"
The gain-of-pigment arm, done in human skin grafted onto a host animal, which is why it is graded MODEL_ORGANISM. Note the review is summarising work it cites rather than reporting its own data.
+ 1 more reference
Upregulated MITF-Driven Melanogenic Transcription
Downstream of the strengthened KIT signal the melanocyte's melanogenic transcriptional program is upregulated, with MITF - the master regulator of the melanocyte lineage and of the pigment-synthesis genes it controls - the most prominently affected node. This step is graded PROVISIONAL rather than ESTABLISHED because the transcriptomic evidence comes from one base-edited cell model of one exon-4 allele, not from patient melanocytes or from the common VTNNV-motif alleles.
epidermal melanocyte CL:2000000 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal melanocyte (CL:2000000). CL:2000000 is a cell type from the Cell Ontology.
positive regulation of melanin biosynthetic process GO:0048023 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased positive regulation of melanin biosynthetic process (GO:0048023). GO:0048023 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Increased Tyrosinase Activity
Show evidence (1 reference)
PMID:41779177 SUPPORT In Vitro
"For de novo c.329 A > G mutation, results showed that the mutation broadly affected the transcription and translation of genes responsible for melanin synthesis, especially the melanin gene MITF."
RNA-sequencing of a base-edited cell model showing the mutant allele reshapes melanin-synthesis gene expression with MITF most affected.
Increased Tyrosinase Activity
The rate-limiting enzyme of melanogenesis runs faster. Tyrosinase activity was significantly higher in cells exposed to the mutant soluble ligand than in cells exposed to wild type. Graded PROVISIONAL rather than ESTABLISHED: this is one 2009 experiment on one allele, and it was done by adding recombinant soluble ligand to A375 melanoma cells rather than in melanocytes expressing the variant from its own locus, so the measurement stands but has not been independently reproduced or shown in a physiological cell context.
epidermal melanocyte CL:2000000 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal melanocyte (CL:2000000). CL:2000000 is a cell type from the Cell Ontology.
tyrosinase activity GO:0004503 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased tyrosinase activity (GO:0004503). GO:0004503 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Increased Melanocyte Melanin Content
Show evidence (1 reference)
PMID:19375057 SUPPORT In Vitro
"Consistent with this result, the tyrosinase activity was significantly increased by mutant sKITLGN36S compared to wild-type control."
The enzymatic measurement - tyrosinase is the rate-limiting step the increased melanin flux passes through.
Increased Melanocyte Melanin Content
The melanocyte accumulates more pigment. Melanin content roughly doubled in cells exposed to the mutant ligand relative to wild type, which is the closest thing in this literature to a direct functional demonstration that the variant is a gain of function on melanin synthesis rather than a rare allele that merely segregates. It carries the same caveat as the tyrosinase measurement above - one paper, one allele, exogenous ligand on a melanoma line - which is why it is PROVISIONAL.
epidermal melanocyte CL:2000000 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal melanocyte (CL:2000000). CL:2000000 is a cell type from the Cell Ontology.
melanin biosynthetic process GO:0042438 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased melanin biosynthetic process (GO:0042438). GO:0042438 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Progressive Epidermal Melanin Accumulation
Show evidence (1 reference)
PMID:19375057 SUPPORT In Vitro
"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."
The quantitative melanin-content measurement, including the cell system it was made in.
Progressive Epidermal Melanin Accumulation
Sustained overproduction of melanin across the epidermis produces the clinical lesion: a diffuse, partly blotchy brown background present at or shortly after birth that enlarges and multiplies with age rather than remitting. The distribution is generalised - face, neck, trunk, and limbs, and frequently the palms, soles, and oral mucosa - and adnexal structures are spared.
pigmentation GO:0043473 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased pigmentation (GO:0043473). GO:0043473 is a biological process from the Gene Ontology. ↑ INCREASED
Animal models
K14-SCF transgenic mouse Mouse partially recapitulates Excess keratinocyte-derived KITLG produces epidermal hyperpigmentation, reproducing the direction of effect but by overexpressing wild-type ligand rather than by the gain-of-function substitution that causes the human disease.
Downstream
Progressive Diffuse Hyperpigmentation
Lentigines
Oral Mucosal Pigmentation
Somatic Reversion of the KITLG Locus in Skin The hyperpigmented background is what makes a reverted clone visible at all - a patch of normally pigmented skin only reads as hypopigmented against it. This edge records that dependency rather than a causal push toward reversion.
Show evidence (2 references)
PMID:19375057 SUPPORT Human Clinical
"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."
The defining clinical course - congenital or early-infantile onset with progression rather than stability.
PMID:33407466 SUPPORT Human Clinical
"hyperpigmented lesions that are intermixed with multiple café-au-lait spots, hypopigmented maculae and lentigines that are located on the face, neck, trunk and limbs and frequently on the palms, soles and oral mucosa"
The anatomical distribution, including acral and mucosal involvement.
Somatic Reversion of the KITLG Locus in Skin
A candidate explanation for the hypopigmented component, and one that would make the "hypo" in the disease name a misnomer. In a patient with hypopigmented macules and striae distributed along the lines of Blaschko, digital PCR found copy-neutral loss of heterozygosity at the KITLG locus in DNA from the pale lesion but not in blood - consistent with clones that lost the mutant allele, reverted to ordinary KITLG-KIT signalling, and appear pale only by contrast with the surrounding hyperpigmented skin. Blaschko-linear distribution is the expected pattern for a clonal somatic event in keratinocyte or melanocyte lineages, which is what makes the observation more than a coincidence. Graded HYPOTHETICAL: this is a single patient carrying a single allele, and the cafe-au-lait macules in the same individual did not follow Blaschko lines and superimposed on the hypopigmented striae, so they require a separate mechanism this one does not supply. The general question is explicitly open in the literature.
epidermal melanocyte CL:2000000 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves epidermal melanocyte (CL:2000000). CL:2000000 is a cell type from the Cell Ontology.
Downstream
Hypopigmented Macules and Streaks
Show evidence (4 references)
PMID:39269165 SUPPORT Human Clinical
"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."
The lesion-restricted copy-neutral LOH and the revertant-mosaicism interpretation drawn from it.
PMID:39269165 SUPPORT Human Clinical
"Conversely, café-au-lait spots do not follow the lines of Blaschko and can superimpose on the hypopigmented striae, indicating a distinct pathogenesis."
The authors' own limitation - reversion explains the pale macules but not the cafe-au-lait macules, so it is not a unified account of the dyspigmentation.
PMID:39269165 SUPPORT Human Clinical
"However, the mechanisms behind hypopigmented macule formation remain unclear."
States that the hypopigmentation mechanism is unresolved, which is why this node is graded HYPOTHETICAL rather than PROVISIONAL.
+ 1 more reference
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Histopathology

1
Increased epidermal melanin, maximal in the basal layer
Biopsy of hyperpigmented skin shows a striking increase in melanin throughout the epidermis, most marked in the basal cell layer, with hypopigmented-area biopsies showing lower epidermal melanin. Histology is supportive rather than diagnostic. Immunohistochemistry in the same biopsies goes further than melanin quantity, and it points somewhere this entry's pathograph does not. S100 and HMB45 staining of the hyperpigmented areas was read as showing increased melanocytes as well as increased melanin - that is, more pigment cells, not only busier ones. The pathograph here models per-melanocyte hyperfunction, because that is what the KITLG functional experiments measure; the histology is evidence for the other reading. Both are recorded, and the conflict is left open rather than resolved by preference. One caution on how far any of this can be pushed: the family it comes from was screened across the entire KITLG coding region and had no mutation. So it describes the FPHH clinical phenotype rather than the KITLG mechanism specifically, and it is cited here for the tissue-level finding and, separately, as evidence of locus heterogeneity.
Show evidence (3 references)
PMID:29186243 SUPPORT Human Clinical
"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"
The histological correlate of both lesion types in one patient.
PMID:29186243 SUPPORT Human Clinical
"These darkly stained regions indicated a large number of melanocytes and melanin"
Immunohistochemical evidence that hyperpigmented skin carries more melanocytes, not merely more pigment per melanocyte - the observation that puts melanocyte hyperplasia in play against the per-melanocyte-hyperfunction model this entry's pathograph uses. The paper itself notes S100 is not melanocyte-specific and may also stain Langerhans cells, which is why the HMB45 result below matters.
PMID:29186243 SUPPORT Human Clinical
"HMB45 staining of the hyperpigmented tissue was similar to that of S100 in the same area with increased melanocytes and melanin"
The same increased-melanocyte finding with a melanocyte-specific marker, which answers the S100 specificity caveat above.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Familial Progressive Hyperpigmentation With Or Without Hypopigmentation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

6
Integument 1
Cafe-au-lait Macules Cafe-au-lait spot HP:0000957 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cafe-au-lait spot (HP:0000957). HP:0000957 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21368769 SUPPORT Human Clinical
"multiple café-au-lait spots, intermingled with scattered hypopigmented-appearing maculae, and lentigines"
Cafe-au-lait macules as a described component of the FPHH phenotype.
PMID:39152874 SUPPORT Human Clinical
"On examination, multiple diffuse lentigines were observed on his face, trunk, and extremities, accompanied by multiple CALMs and scattered hypopigmented macules of varying sizes"
A single-patient examination finding recording cafe-au-lait macules alongside lentigines and hypopigmented macules, and their appearance after the initial hyperpigmentation.
Other 5
Progressive Diffuse Hyperpigmentation VERY_FREQUENT Progressive hyperpigmentation HP:0007505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive hyperpigmentation (HP:0007505), qualified as course progressive; congenital onset. HP:0007505 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE Onset: CONGENITAL
Show evidence (2 references)
PMID:19375057 SUPPORT Human Clinical
"characterized by hyperpigmented patches in the skin, present in early infancy and increasing in size and number with age"
The onset and progression that the phenotype name asserts.
PMID:33407466 SUPPORT Human Clinical
"Generalized hyper- and hypopigmentation with irregular patches was found at birth, and the patches (0.2–0.8 cm) progressed successively over her face, neck, trunk and limbs with age."
A worked pedigree description of congenital onset and progressive spread, with lesion sizes and distribution.
Mixed Hypo- and Hyperpigmentation Mixed hypo- and hyperpigmentation of the skin HP:0009123 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mixed hypo- and hyperpigmentation of the skin (HP:0009123). HP:0009123 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:21368769 SUPPORT Human Clinical
"Clinical signs consist of progressive diffuse, partly blotchy hyperpigmented lesions, multiple café-au-lait spots, intermingled with scattered hypopigmented-appearing maculae, and lentigines."
The full dyspigmentation picture, including the hypopigmented component.
PMID:33407466 SUPPORT Human Clinical
"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"
The morphological range of the mixed pattern.
Hypopigmented Macules and Streaks HP:0020073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypopigmented macule (HP:0020073). HP:0020073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39269165 SUPPORT Human Clinical
"the patient showed multiple hypopigmented macules and striae along the lines of Blaschko"
Documents both the discrete macules and the Blaschko-linear striae.
Lentigines Multiple lentigines HP:0001003 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple lentigines (HP:0001003). HP:0001003 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33407466 SUPPORT Human Clinical
"hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs)"
Lentigines listed among the characteristic lesions, with cafe-au-lait macules noted as only sometimes present.
Oral Mucosal Pigmentation Intra-oral hyperpigmentation HP:0010284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intra-oral hyperpigmentation (HP:0010284). HP:0010284 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:33407466 SUPPORT Human Clinical
"located on the face, neck, trunk and limbs and frequently on the palms, soles and oral mucosa"
Oral mucosal involvement in a molecularly confirmed KITLG series - the primary support, since the case report below was never sequenced.
PMID:22577587 SUPPORT Human Clinical
"hyperpigmented patches in the skin and mucous membranes, present in early infancy, and increase in size and number with age"
Records mucous-membrane involvement as part of the characteristic distribution. Graded PARTIAL because this 2012 case report predates molecular testing in the patient and carries no KITLG genotype, so it cannot be tied to this entry's entity with certainty.
PMID:22577587 SUPPORT Human Clinical
"who presented with a peculiar progressive oral pigmentation disorder"
A worked case in which oral pigmentation was the presenting complaint. Same caveat - clinically diagnosed "FPH", not genotyped.
🧬

Genetic Associations

1
KITLG
Gene: KITLG hgnc:6343 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KITLG (hgnc:6343). hgnc:6343 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (7 references)
PMID:21368769 SUPPORT Human Clinical
"In aggregate, mutations in a single gene cause various pigmentation disorders: FPH, FPHH, and likely DUH2."
The single-gene basis spanning the historically separate FPH, FPHH, and DUH2 concepts - the evidence for treating FPH and FPHH as one entry.
PMID:21368769 SUPPORT Human Clinical
"A reported FPH substitution was observed in two FPHH families, and two, to our knowledge, previously unreported substitutions, p.Val33Ala and p.Thr34Pro, cosegregated with FPHH in two separate families."
The same allele in both phenotypes, which is the specific observation that undermines an FPH/FPHH split.
PMID:21566575 SUPPORT Human Clinical
"Amyere et al. suggest that different pigmentary diseases can result from the same mutation or different mutations in the same gene"
An independent commentary drawing the same conclusion - that phenotypic labels here do not track distinct genetic lesions.
+ 4 more references
🗃️

External Assertions

3
OMIM hyperpigmentation with or without hypopigmentation, familial progressive
OMIM disease record OMIM:145250
The OMIM phenotype entry for the KITLG disease, and the term MONDO:0007771 cross-references. OMIM places the family Wang and colleagues reported as "FPH" - hyperpigmentation only, KITLG p.Asn36Ser - under this entry rather than under its separate FPH1 entry, which is the resource-level statement that the hyper-only presentation belongs to the KITLG entity.
OMIM hyperpigmentation, familial progressive, 1 (FPH1)
OMIM disease record OMIM:614233
The separate OMIM entry for the 19p13.1-pter locus with an unidentified gene. MONDO:0013648 cross-references this, which is why that term is treated here as a differential rather than as a broader synonym of this entry. Recorded because the label "familial progressive hyperpigmentation" is used for both this locus and, loosely, for the KITLG disease.
Orphanet familial progressive hyper- and hypopigmentation
Orphanet disease record ORPHA:280628
The Orphanet concept for the KITLG disease. MONDO:0017239 cross-references it and is placed as a child of MONDO:0007771; on the reading taken here the two MONDO terms describe the same entity from two resources rather than a disease and its subtype.
💊

Medical Actions

1
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
The intervention with the clearest indication, and effectively the only one specific to the disease rather than borrowed from general dyschromia management. Autosomal dominant transmission carries a 50% recurrence risk to offspring, penetrance has been described as reduced, and de novo cases occur - including a demonstrated de novo exon-4 allele - so unaffected parents do not exclude transmissible disease in the proband's own children.
Show evidence (1 reference)
PMID:41779177 SUPPORT Human Clinical
"it would extend the mutation spectrum of KITLG gene. It would improve the disease knowledge base and offer a reliable reference for the clinical diagnosis and prevention of FPHH"
Frames molecular diagnosis as the basis for counselling and prevention. Graded PARTIAL because it argues for the use of genetic information generally rather than reporting a counselling intervention or its outcome.
🌍

Environmental Factors

1
Sun exposure
exposure to ultraviolet radiation ECTO:0000006 Environmental Conditions, Treatments and Exposures Ontology (ECTO) Relation: this environmental factor is this exposure This environmental factor is exposure to ultraviolet radiation (ECTO:0000006). ECTO:0000006 is an exposure from the Environmental Conditions, Treatments and Exposures Ontology.
Ultraviolet exposure deepens existing lesions. It is a modifier of an established genetic disease rather than a cause of it, and it is the only environmental factor reported in this literature - the pedigrees explicitly record no chemical exposure history. It is also the practical reason photoprotection gets recommended even though no photoprotection study exists in this disease.
Show evidence (1 reference)
PMID:29186243 SUPPORT Human Clinical
"For all patients, onset times were between one week and one month after birth, and the lesions deepened after exposure to the sun."
The pedigree-level statement, which also fixes onset in the first month of life.
Mechanism Target:
EXACERBATES Progressive Epidermal Melanin Accumulation — Sun exposure darkens lesional skin further, on top of the constitutive drive from the KITLG variant.
Show evidence (1 reference)
PMID:29186243 SUPPORT Human Clinical
"the lesions deepened after exposure to the sun"
Direct observation across an affected pedigree that UV exposure worsens the pigmentation.
🔬

Diagnosis

2
KITLG sequencing
Targeted sequencing of the KITLG coding region, concentrated on exon 2 where the VTNNV hotspot lies, confirms the clinical diagnosis in most families. Because locus heterogeneity is documented, a negative result does not exclude FPHH.
Show evidence (1 reference)
PMID:36453959 SUPPORT Human Clinical
"High-throughput sequencing revealed that he has harbored a heterozygous c.105T>A (p.Asn35Lys) variant of the KITLG gene, which was unreported previously. Sanger sequencing confirmed that the variant has co-segregated with the disease phenotype in his pedigree."
A worked diagnostic sequence - high-throughput screen followed by Sanger confirmation and cosegregation testing.
Clinical recognition in infancy
The combination of progressive skin pigmentation with hypopigmented spots in an infant is itself the diagnostic trigger, since the lesions are present at or shortly after birth.
Show evidence (1 reference)
PMID:36453959 SUPPORT Human Clinical
"For infants with progressive skin pigmentation and hypopigmentation spots, FPHH should be suspected."
The authors' explicit diagnostic recommendation.
📊

Prevalence

1
Worldwide
Cases In Literature Unknown
No population prevalence estimate exists. The disorder is known from a small number of pedigrees and sporadic cases; as of the 2021 review only eight KITLG mutations had been reported in association with it. No Orphanet epidemiology class is available to cite, so prevalence_class is UNKNOWN rather than a numeric band.
Show evidence (1 reference)
PMID:33407466 SUPPORT Human Clinical
"To date, only eight KITLG mutations have been reported to be associated with FPHH, and no clear genotype-phenotype correlations have been established."
The size of the reported literature, which is the only occurrence figure available.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Familial Progressive Hyperpigmentation With Or Without Hypopigmentation:

Dyschromatosis universalis hereditaria 2
Overlapping Features The nearest neighbour and the hardest to separate. DUH2 maps to the same 12q interval as FPHH, is phenotypically and histologically close to FPH, and Amyere and colleagues judged it likely to be KITLG-related as well. The distinction may not survive further genetics.
Distinguishing Features
  • Maps to the same 12q interval as FPHH
  • Separation currently rests on clinical and histological description rather than on a molecular criterion
Show evidence (1 reference)
PMID:21368769 SUPPORT Human Clinical
"We performed a genome-wide linkage analysis in seven families with FPHH, and identified linkage on 12q21.12-q22, which overlaps with the DUH2 locus."
The shared locus that makes DUH2 the primary differential.
Legius syndrome
Overlapping Features Presents with familial cafe-au-lait macules and skin-fold freckling and is caused by SPRED1 variants. It is raised in the differential because the cafe-au-lait component of FPHH looks similar; the progressive diffuse brown background of FPHH is not part of Legius syndrome.
Distinguishing Features
  • Caused by SPRED1 variants rather than KITLG
  • Skin-fold freckling rather than a progressive diffuse hyperpigmented background
Show evidence (1 reference)
PMID:21368769 SUPPORT Human Clinical
"It also differs from the Legius syndrome, characterized by familial café-au-lait spots and skin fold freckling, caused by mutations in SPRED1."
The authors' own differential, naming the distinguishing gene and features.
Familial progressive hyperpigmentation 1 (FPH1)
Overlapping Features The name collision that matters most for this entry. FPH1 is a dominantly inherited hyperpigmentation-only phenotype mapped by genome screening to 19p13.1-pter in a three-generation Chinese family. Its causal gene has never been identified, and the interval is unrelated to KITLG at 12q. Clinically the two are close - patches present at birth or in early infancy that enlarge and multiply with age - so the separation rests on the locus rather than on the skin.
Distinguishing Features
  • Maps to 19p13.1-pter, not to the KITLG interval at 12q
  • Causal gene unidentified, so it cannot be confirmed by KITLG sequencing
  • No hypopigmented component reported
Show evidence (2 references)
PMID:16709486 SUPPORT Human Clinical
"we identified a locus linked to chromosome 19p13.1-pter responsible for FPH, spanning 45.48 cM between D19S593 and 19pter"
The linkage result establishing FPH1 as a locus distinct from KITLG at 12q.
PMID:16709486 SUPPORT Human Clinical
"Although previous studies showed that FPH is a monogenic trait, the genetic basis for this disease is unknown."
Confirms the FPH1 gene was unidentified, which is why the entity cannot be resolved by molecular testing.
Cafe-au-lait macule and lentigines syndromes
Overlapping Features When the cafe-au-lait and lentigine component is prominent, FPHH is confused with the RASopathy and neurocutaneous disorders that present with multiple cafe-au-lait macules - neurofibromatosis type 1, LEOPARD syndrome, and tuberous sclerosis complex. Legius syndrome belongs to this group too and is listed separately above, because the FPHH literature raises it by name. All of these have extracutaneous features that the genotyped FPHH pedigrees do not report.
Distinguishing Features
  • Progressive diffuse hyperpigmented background, which none of these disorders produces
  • No extracutaneous involvement in FPHH, whereas each of these is a systemic disorder
  • Different causal genes (NF1, SPRED1, PTPN11, TSC1/TSC2) rather than KITLG
Show evidence (1 reference)
PMID:39152874 SUPPORT Human Clinical
"our patient exhibited a relatively large number of CALMs and lentigines which require differentiation from pigmentary diseases that also manifest with multiple CALMs and lentigines, such as neurofibromatosis type 1, legius syndrome, LEOPARD syndrome, and tuberous sclerosis complex"
The authors' stated differential for an FPHH patient in whom the cafe-au-lait and lentigine component dominated.
Biallelic KITLG auditory-pigmentary disorder
Overlapping Features The recessive counterpart at the same gene. Where FPHH is heterozygous gain of function causing excess pigment, biallelic variants cause hypomelanosis - including a sock-and-glove-like symmetric distribution and generalized hypomelanosis - together with sensorineural hearing loss.
Distinguishing Features
  • Biallelic rather than heterozygous KITLG variants
  • Hypomelanosis rather than progressive hyperpigmentation
  • Sensorineural hearing loss, which FPHH does not cause
Show evidence (1 reference)
PMID:35543077 SUPPORT Human Clinical
"we expand the known hypomelanosis spectrum to include a 'sock-and-glove-like', symmetric distribution, progressive repigmentation and generalized hypomelanosis"
The biallelic phenotype, which is hypomelanotic and so the mirror image of FPHH.
🐁

Animal Models

1
K14-SCF transgenic mouse
The closest functional analogue of FPHH, and it is an analogue of the mechanism rather than of the mutation. It puts extra KITLG where FPHH puts overactive KITLG - in the keratinocytes - and the skin responds with epidermal hyperpigmentation, which is the direction FPHH goes. It also speaks to a question this entry leaves open. The pigment increase came with epidermal melanocytosis, meaning more melanocytes in the interfollicular epidermis, so excess keratinocyte KITLG signal can expand the melanocyte population and not merely drive each cell harder. That is the same reading the FPHH immunohistochemistry supports and the opposite of what this entry's pathograph currently models.
Species
Mouse
Genotype
Human keratin 14 promoter driving epidermal keratinocyte expression of stem cell factor (KITLG), in membrane-bound and membrane/soluble transgene variants
Genes
KITLG hgnc:6343 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns KITLG (hgnc:6343). hgnc:6343 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:9584135
Pathograph links
Progressive Epidermal Melanin Accumulation partially recapitulates fidelity: moderate Excess keratinocyte-derived KITLG produces epidermal hyperpigmentation, reproducing the direction of effect but by overexpressing wild-type ligand rather than by the gain-of-function substitution that causes the human disease.
Limitations: Three gaps between this and FPHH. The transgene overexpresses wild-type SCF, so it models too much signal rather than an altered ligand-receptor interface, and it cannot speak to whether the FPHH variants raise binding affinity. Normal mouse interfollicular epidermis has almost no melanocytes, so the baseline being corrected toward is a species difference rather than a disease state - the model makes mouse skin more human-like as much as it makes it FPHH-like. And the membrane/soluble variant also produces cutaneous mastocytosis, which is not a feature of FPHH.
Readouts
Epidermal melanocyte population in interfollicular skin
Direction: INCREASED
Interpretation: Melanocytes maintained in the interadnexal epidermis, where mouse skin does not normally keep them - an increase in melanocyte number rather than in pigment per cell.
Show evidence (1 reference)
PMID:9584135 SUPPORT Model Organism
"Expression of membrane-bound SCF alone resulted in epidermal melanocytosis and melanin production, but did not by itself cause mastocytosis."
The melanocyte-number effect isolated from the mast cell phenotype, in the membrane-bound-only transgene.
Show evidence (1 reference)
PMID:9584135 SUPPORT Model Organism
"caused the maintenance of a population of melanocytes in the interadnexal epidermis, an area where melanocytes and melanin are found in human skin but where they are not typically found in murine skin"
Establishes that keratinocyte KITLG excess drives an epidermal melanocyte population, which is why this model is informative for the human node - and also why its baseline is a species difference rather than a disease state.
Show evidence (1 reference)
PMID:9584135 SUPPORT Model Organism
"we targeted the expression of SCF to epidermal keratinocytes in mice with two different transgenes controlled by the human keratin 14 promoter"
The construct - keratinocyte-targeted KITLG expression, which is the cell compartment FPHH implicates.
{ }

Source YAML

click to show 
name: Familial Progressive Hyperpigmentation With Or Without Hypopigmentation
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
description: >-
  KITLG is the ligand for KIT, and keratinocytes secrete it at melanocytes sitting in the
  same epidermis. The disease-causing variants do not break that signal; they strengthen it.
  Almost all of them fall in a five-residue stretch of exon 2 - the conserved VTNNV motif at
  amino acids 33-37 - which is the surface KITLG presents to its receptor.

  Exactly how a substitution there strengthens the signal is inferred rather than measured:
  homology modelling suggests it raises the ligand's affinity for KIT, and no binding or
  receptor-activation assay on a mutant ligand has been published. What has been measured is
  the output. Adding the mutant soluble ligand to cells raises tyrosinase activity and roughly
  doubles melanin content, and a base-edited model shows the melanogenic transcriptional
  program, MITF included, shifting with it. Clinically that is diffuse hyperpigmentation
  present at or shortly after birth and spreading with age.

  The name carries the disease's central awkwardness. Some families have hyperpigmentation
  and nothing else; others have the same progressive brown background scattered with
  cafe-au-lait macules, lentigines, and pale macules. These were described under separate
  labels - FPH and FPHH - and within KITLG the labels do not track distinct lesions: Amyere
  and colleagues found the p.Asn36Ser allele originally reported in an FPH family segregating
  in two FPHH families, and mapped the whole set to the same 12q interval that dyschromatosis
  universalis hereditaria 2 maps to. Presence or absence of the hypopigmented component is
  therefore treated here as variability within one entity.

  What that argument does not cover is FPH1, which is a different disease with a confusingly
  similar name. A three-generation Chinese family with hyperpigmentation only was mapped to
  19p13.1-pter, nowhere near KITLG, and its gene is still unidentified. So "familial
  progressive hyperpigmentation" names two things: a phenotype label used loosely across the
  KITLG literature, and a specific unsolved 19p locus. Only the first is folded into this
  entry.

  The pale macules are the part that is genuinely not understood, and the most interesting
  recent finding is that they may not be a pigmentary defect at all. In a patient whose
  hypopigmented macules and streaks followed the lines of Blaschko, digital PCR on lesional
  skin found copy-neutral loss of heterozygosity at the KITLG locus present in the pale skin
  and absent from blood - that is, clones that had lost the mutant allele and reverted to
  normal pigmentation, looking pale only against an abnormally dark background. If that
  generalises, "hypopigmentation" in this disease is a misnomer for patches of unaffected
  skin. It is a single patient, and the cafe-au-lait macules in the same person did not
  follow Blaschko lines and so need a different explanation.
disease_term:
  preferred_term: Familial progressive hyperpigmentation with or without hypopigmentation
  term:
    id: MONDO:0007771
    label: hyperpigmentation with or without hypopigmentation, familial progressive
synonyms:
- FPHH
- familial progressive hyper- and hypopigmentation
- hyperpigmentation, familial progressive, 2
- FPH2
- melanosis universalis hereditaria
parents:
- Skin Disorder
- Genodermatosis
external_assertions:
- name: OMIM hyperpigmentation with or without hypopigmentation, familial progressive
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:145250
  url: https://omim.org/entry/145250
  description: >-
    The OMIM phenotype entry for the KITLG disease, and the term MONDO:0007771 cross-references.
    OMIM places the family Wang and colleagues reported as "FPH" - hyperpigmentation only, KITLG
    p.Asn36Ser - under this entry rather than under its separate FPH1 entry, which is the
    resource-level statement that the hyper-only presentation belongs to the KITLG entity.
- name: OMIM hyperpigmentation, familial progressive, 1 (FPH1)
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:614233
  url: https://omim.org/entry/614233
  description: >-
    The separate OMIM entry for the 19p13.1-pter locus with an unidentified gene. MONDO:0013648
    cross-references this, which is why that term is treated here as a differential rather than
    as a broader synonym of this entry. Recorded because the label "familial progressive
    hyperpigmentation" is used for both this locus and, loosely, for the KITLG disease.
- name: Orphanet familial progressive hyper- and hypopigmentation
  source: Orphanet
  assertion_type: disease_record
  external_id: ORPHA:280628
  url: https://www.orpha.net/en/disease/detail/280628
  description: >-
    The Orphanet concept for the KITLG disease. MONDO:0017239 cross-references it and is placed
    as a child of MONDO:0007771; on the reading taken here the two MONDO terms describe the same
    entity from two resources rather than a disease and its subtype.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous KITLG variants segregate with the phenotype through multi-generation
    pedigrees; the founding report followed a six-generation Chinese family. Penetrance has
    been described as reduced, and de novo cases occur - one exon-4 variant was shown to be
    de novo, and a sporadic patient with unaffected parents has been reported carrying the
    recurrent p.Thr34Ile allele.
  evidence:
  - reference: PMID:19375057
    reference_title: Gain-of-function mutation of KIT ligand on melanin synthesis causes familial
      progressive hyperpigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This mutant "G" allele cosegregated perfectly with affected, but not with unaffected,
      members of the FPH family.
    explanation: Cosegregation of the heterozygous KITLG allele with affected status across
      a six-generation pedigree, which is the dominant-inheritance evidence.
  - reference: PMID:21368769
    reference_title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Familial progressive hyper- and hypopigmentation (FPHH) is thought to be an autosomal
      dominant disorder with reduced penetrance.
    explanation: States the dominant mode and flags reduced penetrance; graded PARTIAL because
      the sentence reports the prevailing view rather than a penetrance measurement.
pathophysiology:
- name: KITLG Gain-of-Function Variant in the Receptor-Binding Motif
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    A heterozygous missense substitution in KITLG, almost always within the conserved VTNNV
    motif spanning amino acids 33-37 in exon 2. The motif lies on a conserved beta-strand
    that forms the interface with the KIT receptor, so a substitution there alters the
    ligand-receptor contact rather than destabilising the protein. Reported alleles include
    p.Val33Ala, p.Thr34Pro, p.Thr34Ile, p.Asn35Ile, p.Asn35Lys, p.Asn36Ser, and p.Lys38Thr -
    the last extending the hotspot by one residue, so it is sometimes written VTNNVK, 33-38. Alleles
    outside the motif are also reported: p.Glu113Lys (c.337G>A, exon 4), described as lying at
    a different ligand-receptor interaction site; p.Ser78Leu, reported as novel with no stated
    structural interpretation; and a pair of exon-4 substitutions at c.329A.
  genetic_context:
    gene:
      preferred_term: KITLG
      term:
        id: hgnc:6343
        label: KITLG
    functional_impact_category: GAIN_OF_FUNCTION
    allele_type: missense
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
  molecular_functions:
  - preferred_term: stem cell factor receptor binding
    modifier: INCREASED
    term:
      id: GO:0005173
      label: stem cell factor receptor binding
  cell_types:
  - preferred_term: keratinocyte
    term:
      id: CL:0000312
      label: keratinocyte
  downstream:
  - target: Enhanced KITLG-KIT Signaling in Epidermal Melanocytes
    causal_link_type: DIRECT
  - target: Somatic Reversion of the KITLG Locus in Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reversion is loss of this germline allele in a somatic clone, so the variant is what
      the reversion event acts on. The intermediates - what triggers mitotic recombination
      at this locus, and why it appears to happen often enough to be visible - are unknown.
  evidence:
  - reference: PMID:19375057
    reference_title: Gain-of-function mutation of KIT ligand on melanin synthesis causes familial
      progressive hyperpigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutation profiling of positional candidate genes detected a heterozygous transversion
      (c. 107A-->G) in exon 2 of the KIT ligand (KITLG) gene, predicted to result in the substitution
      of a serine residue for an asparagine residue at codon 36 (p.N-->S).
    explanation: The founding variant, identified by positional cloning after linkage to 12q21.31-q23.1.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Locates the mutational hotspot. Note the source's own hedging - the affinity
      increase is offered as what a mutated motif "may" do, on the basis of homology modelling,
      not as a measured binding result.
  - reference: PMID:21368769
    reference_title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All three mutations were located in a conserved β-strand in KITLG, suggesting
      its important role in the activation of the KITLG receptor c-Kit.
    explanation: Independent confirmation that the FPHH alleles cluster on the conserved receptor-contact
      beta-strand.
  - reference: PMID:32189379
    reference_title: Novel mutation in the KITLG gene in familial progressive hyperpigmentation
      with or without hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We have now identified a novel KITLG mutation, c.337G>A (p.Glu113Lys), in FPHH
      which is located within another ligand-receptor interaction site.
    explanation: Establishes that pathogenic alleles are not confined to the VTNNV motif but
      do remain at ligand-receptor contact surfaces.
- name: Enhanced KITLG-KIT Signaling in Epidermal Melanocytes
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Keratinocyte-derived KITLG binds KIT on neighbouring epidermal melanocytes, dimerising
    the receptor and activating its tyrosine kinase. That this axis is rate-limiting for
    epidermal pigment is well supported: adding soluble KITLG to grafted human skin darkens it,
    and blocking either KITLG or KIT depletes melanocytes.

    What is not established is the step this node names. The proposal is that the mutant ligand
    engages KIT more effectively than wild type, and the sources state it as a possibility
    rather than a finding - the affinity increase is inferred from homology modelling of the
    substituted residues, and no binding assay, receptor phosphorylation measurement, or
    dose-response comparison of mutant against wild-type ligand has been published. Every
    functional experiment in this literature reads out melanin or transcription downstream, not
    receptor engagement itself. The node is graded PROVISIONAL for that reason, and the evidence
    attached below characterises the wild-type axis rather than the mutant's behaviour on it.
  biological_processes:
  - preferred_term: Kit signaling pathway
    modifier: INCREASED
    term:
      id: GO:0038109
      label: Kit signaling pathway
  cell_types:
  - preferred_term: epidermal melanocyte
    term:
      id: CL:2000000
      label: epidermal melanocyte
  downstream:
  - target: Upregulated MITF-Driven Melanogenic Transcription
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:39269165
    reference_title: A case of familial progressive hyperpigmentation with or without hypopigmentation
      presenting with hypopigmented striae along the lines of Blaschko.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: KITLG, expressed by keratinocytes, binds to KIT on melanocytes, stimulating melanogenesis.
      Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH.
    explanation: States the cell-to-cell signalling axis and attributes the diffuse hyperpigmentation
      to its disturbance.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: By KITLG binding, KIT dimerizes and initiates diverse cellular responses and plays
      a crucial role in the development and maintenance of the melanocyte lineage in adult
      skin.
    explanation: The receptor-activation step and its role in maintaining the adult epidermal
      melanocyte lineage.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Injection of the soluble form of sKITLG resulted in hyperpigmentation of the grafted
      skin tissue
    explanation: The gain-of-pigment arm, done in human skin grafted onto a host animal, which is
      why it is graded MODEL_ORGANISM. Note the review is summarising work it cites rather than
      reporting its own data.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: injection of the KIT- or KITLG-blocking antibodies into the explanted human skin
      led to a loss of melanocytes
    explanation: The loss-of-signal arm, done in explanted human skin, hence IN_VITRO. Split from
      the grafted-skin item above so each carries a single evidence_source. Together the two show
      the axis is rate-limiting for epidermal pigmentation in both directions.
- name: Upregulated MITF-Driven Melanogenic Transcription
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Downstream of the strengthened KIT signal the melanocyte's melanogenic transcriptional
    program is upregulated, with MITF - the master regulator of the melanocyte lineage and of
    the pigment-synthesis genes it controls - the most prominently affected node. This step
    is graded PROVISIONAL rather than ESTABLISHED because the transcriptomic evidence comes from
    one base-edited cell model of one exon-4 allele, not from patient melanocytes or from the
    common VTNNV-motif alleles.
  biological_processes:
  - preferred_term: positive regulation of melanin biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0048023
      label: positive regulation of melanin biosynthetic process
  cell_types:
  - preferred_term: epidermal melanocyte
    term:
      id: CL:2000000
      label: epidermal melanocyte
  downstream:
  - target: Increased Tyrosinase Activity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:41779177
    reference_title: New variant in KITLG shapes the pathogenesis of familial progressive hyper-
      and hypo-pigmentation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: For de novo c.329 A > G mutation, results showed that the mutation broadly affected
      the transcription and translation of genes responsible for melanin synthesis, especially
      the melanin gene MITF.
    explanation: RNA-sequencing of a base-edited cell model showing the mutant allele reshapes
      melanin-synthesis gene expression with MITF most affected.
- name: Increased Tyrosinase Activity
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The rate-limiting enzyme of melanogenesis runs faster. Tyrosinase activity was
    significantly higher in cells exposed to the mutant soluble ligand than in cells exposed
    to wild type. Graded PROVISIONAL rather than ESTABLISHED: this is one 2009 experiment on
    one allele, and it was done by adding recombinant soluble ligand to A375 melanoma cells
    rather than in melanocytes expressing the variant from its own locus, so the measurement
    stands but has not been independently reproduced or shown in a physiological cell context.
  molecular_functions:
  - preferred_term: tyrosinase activity
    modifier: INCREASED
    term:
      id: GO:0004503
      label: tyrosinase activity
  cell_types:
  - preferred_term: epidermal melanocyte
    term:
      id: CL:2000000
      label: epidermal melanocyte
  downstream:
  - target: Increased Melanocyte Melanin Content
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:19375057
    reference_title: Gain-of-function mutation of KIT ligand on melanin synthesis causes familial
      progressive hyperpigmentation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Consistent with this result, the tyrosinase activity was significantly increased
      by mutant sKITLGN36S compared to wild-type control.
    explanation: The enzymatic measurement - tyrosinase is the rate-limiting step the increased
      melanin flux passes through.
- name: Increased Melanocyte Melanin Content
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    The melanocyte accumulates more pigment. Melanin content roughly doubled in cells exposed
    to the mutant ligand relative to wild type, which is the closest thing in this literature
    to a direct functional demonstration that the variant is a gain of function on melanin
    synthesis rather than a rare allele that merely segregates. It carries the same caveat as
    the tyrosinase measurement above - one paper, one allele, exogenous ligand on a melanoma
    line - which is why it is PROVISIONAL.
  biological_processes:
  - preferred_term: melanin biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0042438
      label: melanin biosynthetic process
  cell_types:
  - preferred_term: epidermal melanocyte
    term:
      id: CL:2000000
      label: epidermal melanocyte
  downstream:
  - target: Progressive Epidermal Melanin Accumulation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:19375057
    reference_title: Gain-of-function mutation of KIT ligand on melanin synthesis causes familial
      progressive hyperpigmentation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 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.
    explanation: The quantitative melanin-content measurement, including the cell system it was
      made in.
- name: Progressive Epidermal Melanin Accumulation
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Sustained overproduction of melanin across the epidermis produces the clinical lesion: a
    diffuse, partly blotchy brown background present at or shortly after birth that enlarges
    and multiplies with age rather than remitting. The distribution is generalised - face,
    neck, trunk, and limbs, and frequently the palms, soles, and oral mucosa - and adnexal
    structures are spared.
  biological_processes:
  - preferred_term: pigmentation
    modifier: INCREASED
    term:
      id: GO:0043473
      label: pigmentation
  downstream:
  - target: Progressive Diffuse Hyperpigmentation
    causal_link_type: DIRECT
  - target: Lentigines
    causal_link_type: DIRECT
  - target: Oral Mucosal Pigmentation
    causal_link_type: DIRECT
  - target: Somatic Reversion of the KITLG Locus in Skin
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The hyperpigmented background is what makes a reverted clone visible at all - a patch of
      normally pigmented skin only reads as hypopigmented against it. This edge records that
      dependency rather than a causal push toward reversion.
  evidence:
  - reference: PMID:19375057
    reference_title: Gain-of-function mutation of KIT ligand on melanin synthesis causes familial
      progressive hyperpigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: The defining clinical course - congenital or early-infantile onset with progression
      rather than stability.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hyperpigmented lesions that are intermixed with multiple café-au-lait spots, hypopigmented
      maculae and lentigines that are located on the face, neck, trunk and limbs and frequently
      on the palms, soles and oral mucosa
    explanation: The anatomical distribution, including acral and mucosal involvement.
- name: Somatic Reversion of the KITLG Locus in Skin
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    A candidate explanation for the hypopigmented component, and one that would make the
    "hypo" in the disease name a misnomer. In a patient with hypopigmented macules and striae
    distributed along the lines of Blaschko, digital PCR found copy-neutral loss of
    heterozygosity at the KITLG locus in DNA from the pale lesion but not in blood -
    consistent with clones that lost the mutant allele, reverted to ordinary KITLG-KIT
    signalling, and appear pale only by contrast with the surrounding hyperpigmented skin.
    Blaschko-linear distribution is the expected pattern for a clonal somatic event in
    keratinocyte or melanocyte lineages, which is what makes the observation more than a
    coincidence.

    Graded HYPOTHETICAL: this is a single patient carrying a single allele, and the
    cafe-au-lait macules in the same individual did not follow Blaschko lines and superimposed
    on the hypopigmented striae, so they require a separate mechanism this one does not
    supply. The general question is explicitly open in the literature.
  cell_types:
  - preferred_term: epidermal melanocyte
    term:
      id: CL:2000000
      label: epidermal melanocyte
  downstream:
  - target: Hypopigmented Macules and Streaks
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:39269165
    reference_title: A case of familial progressive hyperpigmentation with or without hypopigmentation
      presenting with hypopigmented striae along the lines of Blaschko.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: The lesion-restricted copy-neutral LOH and the revertant-mosaicism interpretation
      drawn from it.
  - reference: PMID:39269165
    reference_title: A case of familial progressive hyperpigmentation with or without hypopigmentation
      presenting with hypopigmented striae along the lines of Blaschko.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Conversely, café-au-lait spots do not follow the lines of Blaschko and can superimpose
      on the hypopigmented striae, indicating a distinct pathogenesis.
    explanation: The authors' own limitation - reversion explains the pale macules but not the
      cafe-au-lait macules, so it is not a unified account of the dyspigmentation.
  - reference: PMID:39269165
    reference_title: A case of familial progressive hyperpigmentation with or without hypopigmentation
      presenting with hypopigmented striae along the lines of Blaschko.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, the mechanisms behind hypopigmented macule formation remain unclear.
    explanation: States that the hypopigmentation mechanism is unresolved, which is why this
      node is graded HYPOTHETICAL rather than PROVISIONAL.
  - reference: PMID:29186243
    reference_title: 'Familial progressive hyper- and hypopigmentation: a report
      on a Chinese family and evidence for genetic heterogeneity.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: The staining for S100 and HMB45 were almost completely negative in the hypopigmentation
      areas.
    explanation: The prediction this node makes is that pale skin holds revertant melanocytes
      pigmenting normally - which requires melanocytes to be present. Here both a general and a
      melanocyte-specific marker are almost absent from hypopigmented skin, meaning the pale
      patches lack melanocytes rather than containing well-behaved ones. Two limits on how far
      it cuts - it is a different family, and one in which no KITLG mutation was found, so it may
      describe a different route to the same clinical picture, and no one has done this staining
      on a lesion shown to carry copy-neutral LOH. It is recorded as REFUTE because it contradicts
      the node's prediction on its face, and it is a substantial part of why the node is graded
      HYPOTHETICAL.
phenotypes:
- category: Dermatologic
  name: Progressive Diffuse Hyperpigmentation
  frequency: VERY_FREQUENT
  diagnostic: true
  description: >-
    The defining and universal feature. Diffuse, partly blotchy hyperpigmented patches
    present at birth or in early infancy, enlarging and increasing in number with age across
    face, neck, trunk, and limbs, and frequently involving palms, soles, and oral mucosa.
  phenotype_term:
    preferred_term: Progressive hyperpigmentation
    term:
      id: HP:0007505
      label: Progressive hyperpigmentation
    clinical_course: PROGRESSIVE
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:19375057
    reference_title: Gain-of-function mutation of KIT ligand on melanin synthesis causes familial
      progressive hyperpigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: characterized by hyperpigmented patches in the skin, present in early infancy
      and increasing in size and number with age
    explanation: The onset and progression that the phenotype name asserts.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Generalized hyper- and hypopigmentation with irregular patches was found at birth,
      and the patches (0.2–0.8 cm) progressed successively over her face, neck, trunk and limbs
      with age.
    explanation: A worked pedigree description of congenital onset and progressive spread, with
      lesion sizes and distribution.
- category: Dermatologic
  name: Mixed Hypo- and Hyperpigmentation
  description: >-
    The feature the disease name qualifies as optional. Scattered pale macules on the
    progressive brown background, ranging from well-isolated patches on normal-appearing skin
    to a confetti-like or mottled pattern. Families in which no hypopigmented feature is
    present were historically separated as FPH; the same KITLG alleles are found in both, so
    this is presentation variability within one entity rather than a second disease.
  phenotype_term:
    preferred_term: Mixed hypo- and hyperpigmentation of the skin
    term:
      id: HP:0009123
      label: Mixed hypo- and hyperpigmentation of the skin
  evidence:
  - reference: PMID:21368769
    reference_title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Clinical signs consist of progressive diffuse, partly blotchy hyperpigmented lesions,
      multiple café-au-lait spots, intermingled with scattered hypopigmented-appearing maculae,
      and lentigines.
    explanation: The full dyspigmentation picture, including the hypopigmented component.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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
    explanation: The morphological range of the mixed pattern.
- category: Dermatologic
  name: Hypopigmented Macules and Streaks
  description: >-
    Discrete pale macules, and in at least one reported patient hypopigmented striae
    following the lines of Blaschko. The Blaschko-linear form is the observation that raised
    revertant mosaicism as the underlying mechanism.
  phenotype_term:
    preferred_term: Hypopigmented macule
    term:
      id: HP:0020073
      label: Hypopigmented macule
  evidence:
  - reference: PMID:39269165
    reference_title: A case of familial progressive hyperpigmentation with or without hypopigmentation
      presenting with hypopigmented striae along the lines of Blaschko.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the patient showed multiple hypopigmented macules and striae along the lines of
      Blaschko
    explanation: Documents both the discrete macules and the Blaschko-linear striae.
- category: Dermatologic
  name: Cafe-au-lait Macules
  description: >-
    Multiple cafe-au-lait macules superimposed on the hyperpigmented background. Their
    presence is the main reason FPHH is confused with neurofibromatosis type 1 and with
    Legius syndrome, and in the one patient studied for it they did not share the
    Blaschko-linear distribution of the pale lesions, implying a separate pathogenesis.
  phenotype_term:
    preferred_term: Cafe-au-lait spot
    term:
      id: HP:0000957
      label: Cafe-au-lait spot
  evidence:
  - reference: PMID:21368769
    reference_title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: multiple café-au-lait spots, intermingled with scattered hypopigmented-appearing
      maculae, and lentigines
    explanation: Cafe-au-lait macules as a described component of the FPHH phenotype.
  - reference: PMID:39152874
    reference_title: A novel KITLG mutation causes familial progressive hyperpigmentation and
      hypopigmentation with multiple café-au-lait macules.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: On examination, multiple diffuse lentigines were observed on his face, trunk, and
      extremities, accompanied by multiple CALMs and scattered hypopigmented macules of varying
      sizes
    explanation: A single-patient examination finding recording cafe-au-lait macules alongside
      lentigines and hypopigmented macules, and their appearance after the initial hyperpigmentation.
- category: Dermatologic
  name: Lentigines
  description: >-
    Small, sharply demarcated dark macules scattered among the other lesions. The one source
    that ranks the lesions puts lentigines ahead of cafe-au-lait macules, which it calls only
    sometimes present; neither is quantified, so no frequency band is asserted here.
  phenotype_term:
    preferred_term: Multiple lentigines
    term:
      id: HP:0001003
      label: Multiple lentigines
  evidence:
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hypopigmented spots, lentigines and sometimes Cafe-au-lait spots (CALs)
    explanation: Lentigines listed among the characteristic lesions, with cafe-au-lait macules
      noted as only sometimes present.
- category: Dermatologic
  name: Oral Mucosal Pigmentation
  description: >-
    Pigmentation of the oral mucosa alongside the cutaneous lesions. It is the feature most
    likely to bring a patient to a dentist rather than a dermatologist, and its presence is
    part of why Peutz-Jeghers syndrome and Addison disease sit in the differential. No
    frequency band is given: the KITLG series describe mucosal involvement as frequent while
    the same paper reports a pedigree with no mucosal disease, and there is no denominator
    anywhere in this literature to adjudicate between them.
  phenotype_term:
    preferred_term: Intra-oral hyperpigmentation
    term:
      id: HP:0010284
      label: Intra-oral hyperpigmentation
  evidence:
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: located on the face, neck, trunk and limbs and frequently on the palms, soles and
      oral mucosa
    explanation: Oral mucosal involvement in a molecularly confirmed KITLG series - the primary
      support, since the case report below was never sequenced.
  - reference: PMID:22577587
    reference_title: 'Familial progressive hyperpigmentation: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: hyperpigmented patches in the skin and mucous membranes, present in early infancy,
      and increase in size and number with age
    explanation: Records mucous-membrane involvement as part of the characteristic distribution.
      Graded PARTIAL because this 2012 case report predates molecular testing in the patient and
      carries no KITLG genotype, so it cannot be tied to this entry's entity with certainty.
  - reference: PMID:22577587
    reference_title: 'Familial progressive hyperpigmentation: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: who presented with a peculiar progressive oral pigmentation disorder
    explanation: A worked case in which oral pigmentation was the presenting complaint. Same
      caveat - clinically diagnosed "FPH", not genotyped.
histopathology:
- name: Increased epidermal melanin, maximal in the basal layer
  description: >-
    Biopsy of hyperpigmented skin shows a striking increase in melanin throughout the
    epidermis, most marked in the basal cell layer, with hypopigmented-area biopsies showing
    lower epidermal melanin. Histology is supportive rather than diagnostic.

    Immunohistochemistry in the same biopsies goes further than melanin quantity, and it
    points somewhere this entry's pathograph does not. S100 and HMB45 staining of the
    hyperpigmented areas was read as showing increased melanocytes as well as increased
    melanin - that is, more pigment cells, not only busier ones. The pathograph here models
    per-melanocyte hyperfunction, because that is what the KITLG functional experiments
    measure; the histology is evidence for the other reading. Both are recorded, and the
    conflict is left open rather than resolved by preference.

    One caution on how far any of this can be pushed: the family it comes from was screened
    across the entire KITLG coding region and had no mutation. So it describes the FPHH
    clinical phenotype rather than the KITLG mechanism specifically, and it is cited here for
    the tissue-level finding and, separately, as evidence of locus heterogeneity.
  evidence:
  - reference: PMID:29186243
    reference_title: 'Familial progressive hyper- and hypopigmentation: a report
      on a Chinese family and evidence for genetic heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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
    explanation: The histological correlate of both lesion types in one patient.
  - reference: PMID:29186243
    reference_title: 'Familial progressive hyper- and hypopigmentation: a report
      on a Chinese family and evidence for genetic heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: These darkly stained regions indicated a large number of melanocytes and melanin
    explanation: Immunohistochemical evidence that hyperpigmented skin carries more melanocytes,
      not merely more pigment per melanocyte - the observation that puts melanocyte hyperplasia
      in play against the per-melanocyte-hyperfunction model this entry's pathograph uses. The
      paper itself notes S100 is not melanocyte-specific and may also stain Langerhans cells,
      which is why the HMB45 result below matters.
  - reference: PMID:29186243
    reference_title: 'Familial progressive hyper- and hypopigmentation: a report
      on a Chinese family and evidence for genetic heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: HMB45 staining of the hyperpigmented tissue was similar to that of S100 in the same
      area with increased melanocytes and melanin
    explanation: The same increased-melanocyte finding with a melanocyte-specific marker, which
      answers the S100 specificity caveat above.
genetic:
- name: KITLG
  gene_term:
    preferred_term: KITLG
    term:
      id: hgnc:6343
      label: KITLG
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Two things about this gene make the entry's scope decisions turn on it.

    First, direction of effect determines which KITLG disease a patient has. The FPHH alleles
    are heterozygous gain-of-function substitutions at the receptor-binding surface, and they
    cause too much pigment. Biallelic KITLG variants do the opposite: loss-of-function pairs
    have been proposed to cause generalized hypomelanosis, and residual-function pairs a
    variable auditory-pigmentary disorder resembling Waardenburg syndrome type 2 or
    piebaldism. That recessive disorder is a separate entity, not a severity band of this one,
    and it is kept out of this entry.

    Second, the same gene and in one case the same allele underlie concepts that are carried as
    distinct terms. p.Asn36Ser was reported first in a family labelled FPH - hyperpigmentation
    only - and then found segregating in two FPHH families, and the FPHH locus overlaps that of
    dyschromatosis universalis hereditaria 2. This entry therefore treats the hyper-only and
    hyper-plus-hypo presentations as one KITLG disease with a variable hypopigmented component.
    This argument is confined to KITLG and does not extend to FPH1 (OMIM:614233), which is a
    separate 19p13.1-pter locus with no identified gene.

    Locus heterogeneity is real and unresolved: FPHH families without any KITLG mutation have
    been reported, so a negative KITLG result does not exclude the clinical diagnosis.
  evidence:
  - reference: PMID:21368769
    reference_title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'In aggregate, mutations in a single gene cause various pigmentation disorders:
      FPH, FPHH, and likely DUH2.'
    explanation: The single-gene basis spanning the historically separate FPH, FPHH, and DUH2
      concepts - the evidence for treating FPH and FPHH as one entry.
  - reference: PMID:21368769
    reference_title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A reported FPH substitution was observed in two FPHH families, and two, to our
      knowledge, previously unreported substitutions, p.Val33Ala and p.Thr34Pro, cosegregated
      with FPHH in two separate families.
    explanation: The same allele in both phenotypes, which is the specific observation that
      undermines an FPH/FPHH split.
  - reference: PMID:21566575
    reference_title: 'The genetic determination of skin pigmentation: KITLG and the KITLG/c-Kit
      pathway as key players in the onset of human familial pigmentary diseases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Amyere et al. suggest that different pigmentary diseases can result from the same
      mutation or different mutations in the same gene
    explanation: An independent commentary drawing the same conclusion - that phenotypic labels
      here do not track distinct genetic lesions.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, many FPHH families without KITLG mutations have been identified, indicating
      additional locus heterogeneity for this disorder
    explanation: Documents that KITLG does not account for all clinically diagnosed FPHH.
  - reference: PMID:29186243
    reference_title: 'Familial progressive hyper- and hypopigmentation: a report
      on a Chinese family and evidence for genetic heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Analysis revealed that its members did not have any mutations of the KITLG gene,
      which provided evidence for genetic heterogeneity of this genodermatosis.
    explanation: A worked KITLG-negative FPHH family - the concrete instance behind the locus
      heterogeneity claim, and the reason a negative KITLG result cannot exclude the diagnosis.
  - reference: PMID:35543077
    reference_title: Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and
      sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We provide consolidating evidence that biallelic KITLG variants cause a distinct
      auditory-pigmentary disorder.
    explanation: Establishes the biallelic disorder as a separate entity, supporting its exclusion
      from this entry.
  - reference: PMID:35543077
    reference_title: Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and
      sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Pathogenic variants in KITLG, a crucial protein involved in pigmentation and neural
      crest cell migration, cause non-syndromic hearing loss, Waardenburg syndrome type 2, familial
      progressive hyperpigmentation and familial progressive hyper- and hypopigmentation, all
      of which are inherited in an autosomal dominant manner.
    explanation: The full allelic series at KITLG, which is what the differential for this entry
      has to be drawn against.
differential_diagnoses:
- name: Dyschromatosis universalis hereditaria 2
  description: >-
    The nearest neighbour and the hardest to separate. DUH2 maps to the same 12q interval as
    FPHH, is phenotypically and histologically close to FPH, and Amyere and colleagues judged
    it likely to be KITLG-related as well. The distinction may not survive further genetics.
  distinguishing_features:
  - Maps to the same 12q interval as FPHH
  - Separation currently rests on clinical and histological description rather than on a molecular criterion
  evidence:
  - reference: PMID:21368769
    reference_title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We performed a genome-wide linkage analysis in seven families with FPHH, and identified
      linkage on 12q21.12-q22, which overlaps with the DUH2 locus.
    explanation: The shared locus that makes DUH2 the primary differential.
- name: Legius syndrome
  description: >-
    Presents with familial cafe-au-lait macules and skin-fold freckling and is caused by
    SPRED1 variants. It is raised in the differential because the cafe-au-lait component of
    FPHH looks similar; the progressive diffuse brown background of FPHH is not part of
    Legius syndrome.
  distinguishing_features:
  - Caused by SPRED1 variants rather than KITLG
  - Skin-fold freckling rather than a progressive diffuse hyperpigmented background
  evidence:
  - reference: PMID:21368769
    reference_title: KITLG mutations cause familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It also differs from the Legius syndrome, characterized by familial café-au-lait
      spots and skin fold freckling, caused by mutations in SPRED1.
    explanation: The authors' own differential, naming the distinguishing gene and features.
- name: Familial progressive hyperpigmentation 1 (FPH1)
  description: >-
    The name collision that matters most for this entry. FPH1 is a dominantly inherited
    hyperpigmentation-only phenotype mapped by genome screening to 19p13.1-pter in a
    three-generation Chinese family. Its causal gene has never been identified, and the
    interval is unrelated to KITLG at 12q. Clinically the two are close - patches present at
    birth or in early infancy that enlarge and multiply with age - so the separation rests on
    the locus rather than on the skin.
  distinguishing_features:
  - Maps to 19p13.1-pter, not to the KITLG interval at 12q
  - Causal gene unidentified, so it cannot be confirmed by KITLG sequencing
  - No hypopigmented component reported
  evidence:
  - reference: PMID:16709486
    reference_title: Linkage of a locus determining familial progressive hyperpigmentation (FPH)
      to chromosome 19p13.1-pter in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified a locus linked to chromosome 19p13.1-pter responsible for FPH, spanning
      45.48 cM between D19S593 and 19pter
    explanation: The linkage result establishing FPH1 as a locus distinct from KITLG at 12q.
  - reference: PMID:16709486
    reference_title: Linkage of a locus determining familial progressive hyperpigmentation (FPH)
      to chromosome 19p13.1-pter in a Chinese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Although previous studies showed that FPH is a monogenic trait, the genetic basis
      for this disease is unknown.
    explanation: Confirms the FPH1 gene was unidentified, which is why the entity cannot be resolved
      by molecular testing.
- name: Cafe-au-lait macule and lentigines syndromes
  description: >-
    When the cafe-au-lait and lentigine component is prominent, FPHH is confused with the
    RASopathy and neurocutaneous disorders that present with multiple cafe-au-lait macules -
    neurofibromatosis type 1, LEOPARD syndrome, and tuberous sclerosis complex. Legius
    syndrome belongs to this group too and is listed separately above, because the FPHH
    literature raises it by name. All of these have extracutaneous features that the
    genotyped FPHH pedigrees do not report.
  distinguishing_features:
  - Progressive diffuse hyperpigmented background, which none of these disorders produces
  - No extracutaneous involvement in FPHH, whereas each of these is a systemic disorder
  - Different causal genes (NF1, SPRED1, PTPN11, TSC1/TSC2) rather than KITLG
  evidence:
  - reference: PMID:39152874
    reference_title: A novel KITLG mutation causes familial progressive hyperpigmentation and
      hypopigmentation with multiple café-au-lait macules.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: our patient exhibited a relatively large number of CALMs and lentigines which require
      differentiation from pigmentary diseases that also manifest with multiple CALMs and lentigines,
      such as neurofibromatosis type 1, legius syndrome, LEOPARD syndrome, and tuberous sclerosis
      complex
    explanation: The authors' stated differential for an FPHH patient in whom the cafe-au-lait
      and lentigine component dominated.
- name: Biallelic KITLG auditory-pigmentary disorder
  description: >-
    The recessive counterpart at the same gene. Where FPHH is heterozygous gain of function
    causing excess pigment, biallelic variants cause hypomelanosis - including a
    sock-and-glove-like symmetric distribution and generalized hypomelanosis - together with
    sensorineural hearing loss.
  distinguishing_features:
  - Biallelic rather than heterozygous KITLG variants
  - Hypomelanosis rather than progressive hyperpigmentation
  - Sensorineural hearing loss, which FPHH does not cause
  evidence:
  - reference: PMID:35543077
    reference_title: Biallelic KITLG variants lead to a distinct spectrum of hypomelanosis and
      sensorineural hearing loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we expand the known hypomelanosis spectrum to include a 'sock-and-glove-like',
      symmetric distribution, progressive repigmentation and generalized hypomelanosis
    explanation: The biallelic phenotype, which is hypomelanotic and so the mirror image of FPHH.
diagnosis:
- name: KITLG sequencing
  description: >-
    Targeted sequencing of the KITLG coding region, concentrated on exon 2 where the VTNNV
    hotspot lies, confirms the clinical diagnosis in most families. Because locus
    heterogeneity is documented, a negative result does not exclude FPHH.
  evidence:
  - reference: PMID:36453959
    reference_title: '[Clinical phenotype and genetic analysis of a Chinese pedigree affected
      with familial progressive hyperpigmentation and hypopigmentation].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: High-throughput sequencing revealed that he has harbored a heterozygous c.105T>A
      (p.Asn35Lys) variant of the KITLG gene, which was unreported previously. Sanger sequencing
      confirmed that the variant has co-segregated with the disease phenotype in his pedigree.
    explanation: A worked diagnostic sequence - high-throughput screen followed by Sanger confirmation
      and cosegregation testing.
- name: Clinical recognition in infancy
  description: >-
    The combination of progressive skin pigmentation with hypopigmented spots in an infant is
    itself the diagnostic trigger, since the lesions are present at or shortly after birth.
  evidence:
  - reference: PMID:36453959
    reference_title: '[Clinical phenotype and genetic analysis of a Chinese pedigree affected
      with familial progressive hyperpigmentation and hypopigmentation].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: For infants with progressive skin pigmentation and hypopigmentation spots, FPHH
      should be suspected.
    explanation: The authors' explicit diagnostic recommendation.
animal_models:
- name: K14-SCF transgenic mouse
  species: Mouse
  genotype: Human keratin 14 promoter driving epidermal keratinocyte expression of stem cell
    factor (KITLG), in membrane-bound and membrane/soluble transgene variants
  description: >-
    The closest functional analogue of FPHH, and it is an analogue of the mechanism rather
    than of the mutation. It puts extra KITLG where FPHH puts overactive KITLG - in the
    keratinocytes - and the skin responds with epidermal hyperpigmentation, which is the
    direction FPHH goes.

    It also speaks to a question this entry leaves open. The pigment increase came with
    epidermal melanocytosis, meaning more melanocytes in the interfollicular epidermis, so
    excess keratinocyte KITLG signal can expand the melanocyte population and not merely drive
    each cell harder. That is the same reading the FPHH immunohistochemistry supports and the
    opposite of what this entry's pathograph currently models.
  publication: PMID:9584135
  genes:
  - preferred_term: KITLG
    term:
      id: hgnc:6343
      label: KITLG
  modeled_mechanisms:
  - target: Progressive Epidermal Melanin Accumulation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Excess keratinocyte-derived KITLG produces epidermal hyperpigmentation, reproducing the
      direction of effect but by overexpressing wild-type ligand rather than by the
      gain-of-function substitution that causes the human disease.
    limitations: >-
      Three gaps between this and FPHH. The transgene overexpresses wild-type SCF, so it models
      too much signal rather than an altered ligand-receptor interface, and it cannot speak to
      whether the FPHH variants raise binding affinity. Normal mouse interfollicular epidermis
      has almost no melanocytes, so the baseline being corrected toward is a species difference
      rather than a disease state - the model makes mouse skin more human-like as much as it
      makes it FPHH-like. And the membrane/soluble variant also produces cutaneous mastocytosis,
      which is not a feature of FPHH.
    readouts:
    - name: Epidermal melanocyte population in interfollicular skin
      target: Progressive Epidermal Melanin Accumulation
      direction: INCREASED
      interpretation: >-
        Melanocytes maintained in the interadnexal epidermis, where mouse skin does not normally
        keep them - an increase in melanocyte number rather than in pigment per cell.
      evidence:
      - reference: PMID:9584135
        reference_title: Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Expression of membrane-bound SCF alone resulted in epidermal melanocytosis and
          melanin production, but did not by itself cause mastocytosis.
        explanation: The melanocyte-number effect isolated from the mast cell phenotype, in the
          membrane-bound-only transgene.
    evidence:
    - reference: PMID:9584135
      reference_title: Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: caused the maintenance of a population of melanocytes in the interadnexal epidermis,
        an area where melanocytes and melanin are found in human skin but where they are not typically
        found in murine skin
      explanation: Establishes that keratinocyte KITLG excess drives an epidermal melanocyte
        population, which is why this model is informative for the human node - and also why its
        baseline is a species difference rather than a disease state.
  evidence:
  - reference: PMID:9584135
    reference_title: Murine cutaneous mastocytosis and epidermal melanocytosis induced by keratinocyte expression of transgenic stem cell factor.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we targeted the expression of SCF to epidermal keratinocytes in mice with two different
      transgenes controlled by the human keratin 14 promoter
    explanation: The construct - keratinocyte-targeted KITLG expression, which is the cell
      compartment FPHH implicates.
environmental:
- name: Sun exposure
  description: >-
    Ultraviolet exposure deepens existing lesions. It is a modifier of an established
    genetic disease rather than a cause of it, and it is the only environmental factor
    reported in this literature - the pedigrees explicitly record no chemical exposure
    history. It is also the practical reason photoprotection gets recommended even though
    no photoprotection study exists in this disease.
  exposure_term:
    preferred_term: exposure to ultraviolet radiation
    term:
      id: ECTO:0000006
      label: exposure to ultraviolet radiation
  influences_mechanisms:
  - target: Progressive Epidermal Melanin Accumulation
    environmental_effect: EXACERBATES
    causal_link_type: DIRECT
    description: >-
      Sun exposure darkens lesional skin further, on top of the constitutive drive from the
      KITLG variant.
    evidence:
    - reference: PMID:29186243
      reference_title: 'Familial progressive hyper- and hypopigmentation: a report
        on a Chinese family and evidence for genetic heterogeneity.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the lesions deepened after exposure to the sun
      explanation: Direct observation across an affected pedigree that UV exposure worsens the
        pigmentation.
  evidence:
  - reference: PMID:29186243
    reference_title: 'Familial progressive hyper- and hypopigmentation: a report
      on a Chinese family and evidence for genetic heterogeneity.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: For all patients, onset times were between one week and one month after birth, and
      the lesions deepened after exposure to the sun.
    explanation: The pedigree-level statement, which also fixes onset in the first month of life.
treatments:
- name: Genetic Counseling
  description: >-
    The intervention with the clearest indication, and effectively the only one specific to the
    disease rather than borrowed from general dyschromia management. Autosomal dominant
    transmission carries a 50% recurrence risk to offspring, penetrance has been described as
    reduced, and de novo cases occur - including a demonstrated de novo exon-4 allele - so
    unaffected parents do not exclude transmissible disease in the proband's own children.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41779177
    reference_title: New variant in KITLG shapes the pathogenesis of familial progressive hyper-
      and hypo-pigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: it would extend the mutation spectrum of KITLG gene. It would improve the disease
      knowledge base and offer a reliable reference for the clinical diagnosis and prevention
      of FPHH
    explanation: Frames molecular diagnosis as the basis for counselling and prevention. Graded
      PARTIAL because it argues for the use of genetic information generally rather than reporting
      a counselling intervention or its outcome.
  notes: >-
    No trial, series, or outcome data exist for any intervention in this disease. This entry
    records genetic counselling because it follows directly from the established inheritance
    pattern, and deliberately does not curate the cosmetic and depigmenting measures
    (photoprotection, topical lightening agents, Q-switched laser) that appear in the general
    hyperpigmentation literature: none has been reported in FPHH, and extrapolating them here
    would manufacture a treatment section out of inference.

    KIT inhibition is the mechanistically obvious idea and is deliberately not curated as a
    treatment. Imatinib does suppress melanogenesis and does cause depigmentation in treated
    patients, but no one has given it for this indication, systemic KIT inhibition for a benign
    cosmetic condition is not a defensible trade, and no topical or intralesional agent exists.
    It belongs in a hypothesis, not in this list.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence estimate exists. The disorder is known from a small number of
    pedigrees and sporadic cases; as of the 2021 review only eight KITLG mutations had been
    reported in association with it. No Orphanet epidemiology class is available to cite, so
    prevalence_class is UNKNOWN rather than a numeric band.
  evidence:
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To date, only eight KITLG mutations have been reported to be associated with FPHH,
      and no clear genotype-phenotype correlations have been established.
    explanation: The size of the reported literature, which is the only occurrence figure available.
discussions:
- discussion_id: fphh_hypopigmentation_reversion
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do the hypopigmented macules of FPHH represent a pigmentary defect, or are they revertant
    clones that have lost the mutant KITLG allele and simply look pale against hyperpigmented
    skin?
  attaches_to:
  - pathophysiology#Somatic Reversion of the KITLG Locus in Skin
  - phenotypes#Hypopigmented Macules and Streaks
  rationale: >-
    The answer changes what the disease is. If the pale lesions are revertant clones, the
    "with or without hypopigmentation" in the disease name describes a secondary somatic
    phenomenon rather than a second primary lesion, and the FPH/FPHH split collapses further -
    FPHH would be FPH plus reversion events. The single supporting observation is
    lesion-restricted copy-neutral loss of heterozygosity in Blaschko-linear striae in one
    patient, and the same paper notes that the cafe-au-lait macules do not follow Blaschko
    lines, so reversion cannot be the whole account of the dyspigmentation.
  proposed_experiments:
  - experiment_id: fphh_lesional_allele_ratio
    name: Lesion-restricted allele-ratio testing across an FPHH cohort
    description: >-
      Digital PCR or deep amplicon sequencing of the causal KITLG allele in matched
      hypopigmented lesional skin, adjacent hyperpigmented skin, and blood from multiple
      unrelated FPHH patients carrying different alleles, to establish whether copy-neutral
      LOH in pale lesions is general or was a single-patient finding.
    would_support:
    - pathophysiology#Somatic Reversion of the KITLG Locus in Skin
    supporting_outcome:
    - Loss of the mutant allele restricted to hypopigmented lesional skin in a substantial
      fraction of patients, absent from adjacent hyperpigmented skin and from blood.
    would_refute:
    - pathophysiology#Somatic Reversion of the KITLG Locus in Skin
    refuting_outcome:
    - Mutant allele retained at germline ratio in hypopigmented lesions across the cohort,
      indicating the pale macules arise by a mechanism other than reversion.
- discussion_id: fphh_kitlg_negative_locus_heterogeneity
  kind: KNOWLEDGE_GAP
  prompt: >-
    What accounts for FPHH in the families in which no KITLG variant is found?
  attaches_to:
  - genetic#KITLG
  rationale: >-
    Locus heterogeneity is documented but no second gene has been identified. Since KITLG acts
    through KIT and the melanogenic transcriptional program it drives, variants elsewhere on
    that axis are the obvious candidates, but this has not been shown. Practically, it means a
    negative KITLG test cannot exclude the diagnosis.
  proposed_experiments:
  - experiment_id: fphh_kitlg_negative_exome
    name: Exome or genome sequencing of KITLG-negative FPHH pedigrees
    description: >-
      Unbiased sequencing of multiplex families meeting FPHH clinical criteria in whom KITLG
      coding sequence is normal, with attention to KIT and to MITF-pathway melanogenic
      regulators.
    would_support:
    - pathophysiology#Enhanced KITLG-KIT Signaling in Epidermal Melanocytes
    supporting_outcome:
    - Identification of segregating variants in a second gene on the KITLG-KIT-MITF axis,
      which would confirm the pathway while establishing the disorder as genetically
      heterogeneous.
- discussion_id: fphh_hyperplasia_vs_hyperfunction
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the hyperpigmentation of FPHH caused by more melanocytes, or by the same number of
    melanocytes each making more pigment?
  attaches_to:
  - pathophysiology#Increased Melanocyte Melanin Content
  - histopathology#Increased epidermal melanin, maximal in the basal layer
  - animal_models#Mouse
  rationale: >-
    The two lines of evidence in this entry point different ways, and the entry commits to one
    of them in its pathograph, so the disagreement should be visible rather than buried.

    The functional work measures output per cell: adding mutant soluble ligand to a melanoma
    line raised tyrosinase activity and roughly doubled melanin content, with no claim about
    cell number. That is hyperfunction, and it is what the pathograph models. The
    immunohistochemistry points the other way: S100 and HMB45 staining of hyperpigmented skin
    was read as showing increased melanocytes as well as increased melanin. KITLG-KIT signalling
    is known to drive melanocyte proliferation as well as pigment production, so a
    gain-of-function ligand could plausibly do both, and the two readings are not mutually
    exclusive.

    A third line points the same way as the histology. Targeting KITLG expression to
    keratinocytes in mice produces epidermal melanocytosis - more melanocytes in the
    interfollicular epidermis - alongside the increased pigment, so an excess keratinocyte
    signal demonstrably can expand the population rather than only drive it harder.

    Neither observation settles it. The functional experiment used exogenous ligand on a cell
    line and could not have detected a proliferative effect in skin. The histology came from a
    family in which no KITLG mutation was found, so it may not describe this entity's mechanism
    at all. The mouse overexpresses wild-type ligand and starts from an epidermis that normally
    has no interfollicular melanocytes at all. What is missing is a melanocyte count in
    genotyped patient skin.
  proposed_experiments:
  - experiment_id: fphh_melanocyte_density
    name: Melanocyte density in genotyped FPHH skin
    description: >-
      Quantitative melanocyte counts, by melanocyte-specific immunohistochemistry on
      standardised biopsy fields, comparing lesional hyperpigmented skin against non-lesional
      skin from the same patient and against matched controls, in patients with a confirmed
      KITLG variant.
    would_support:
    - pathophysiology#Increased Melanocyte Melanin Content
    supporting_outcome:
    - Melanocyte density in lesional skin indistinguishable from non-lesional and control skin,
      leaving increased melanin per cell as the explanation and confirming the pathograph as
      modelled.
    would_refute:
    - pathophysiology#Increased Melanocyte Melanin Content
    refuting_outcome:
    - Melanocyte density significantly raised in lesional skin, indicating the pigment excess is
      at least partly a proliferative effect and requiring a melanocyte-proliferation node the
      pathograph does not currently have.
- discussion_id: fphh_extracutaneous_involvement
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is FPHH strictly skin-limited, or do the extracutaneous features reported in some pedigrees
    belong to the KITLG disease?
  attaches_to:
  - phenotypes#Progressive Diffuse Hyperpigmentation
  - genetic#KITLG
  rationale: >-
    This entry curates no systemic phenotype, and that is a decision rather than a finding.
    On one side, an affected pedigree was explicitly reported to have no other skin, nail,
    hair, teeth, mucosal, or systemic disease. On the other, the same review's survey of
    reported families records sparse lateral eyebrows and malignancy in two families and short
    sutures in one, and older pre-molecular reports under the "melanosis universalis
    hereditaria" label describe growth and developmental abnormalities. The negative comes from
    a single pedigree and cannot carry a disease-level claim; the positives are mostly from
    families that were never genotyped, in an era when the label was applied loosely and when
    what is now known to be a separate 19p disease was not distinguishable. Until genotyped
    series report systematically on extracutaneous findings, neither "skin-limited" nor
    "syndromic" is supportable, so the entry asserts neither.
  evidence:
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All the affected individuals in this family had similar lesions, and none of them
      showed any other skin, nail, hair, teeth, mucosal or systemic diseases.
    explanation: The skin-limited observation. Graded PARTIAL because it is scoped to one family
      by its own wording and cannot establish a disease-level negative.
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sparse lateral eyebrows and malignancy (pharyngeal cancer, papillary thyroid cancer
      and melanoma) were found in two families. Short sutures were found in only one family, and
      mental retardation was not present in these FPHH patients
    explanation: The contrary observations from the same survey, including its own negative on
      intellectual disability - which is what the older syndromic reports had claimed.
- discussion_id: fphh_malignancy_risk
  kind: KNOWLEDGE_GAP
  prompt: >-
    Do KITLG gain-of-function alleles carry any increased risk of melanoma or other malignancy,
    or is the reported cancer an artefact of small numbers?
  attaches_to:
  - genetic#KITLG
  - clinical_burden#
  rationale: >-
    Malignancy - pharyngeal cancer, papillary thyroid cancer, and melanoma - was noted in two of
    the reported FPHH families, while the six-generation index family had none. Gain-of-function
    mutations in KIT, the receptor this ligand activates, cause gastrointestinal stromal tumour,
    so a neoplastic effect of chronic pathway activation is not implausible on its face. But the
    total reported literature is a few dozen patients, cancers of these types occur in unselected
    families, and no age-adjusted comparison has been made. This is recorded as an open question
    specifically so that it is not curated as an established complication, which would put
    surveillance recommendations on a single uncontrolled observation.
  evidence:
  - reference: PMID:33407466
    reference_title: Identification of a novel mutation in the KITLG gene
      in a Chinese family with familial progressive hyper- and hypopigmentation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sparse lateral eyebrows and malignancy (pharyngeal cancer, papillary thyroid cancer
      and melanoma) were found in two families.
    explanation: The observation that raises the question. Graded PARTIAL because it is an
      uncontrolled tally across two reported families with no denominator or population comparison,
      so it supports opening the question rather than an association.
  proposed_experiments:
  - experiment_id: fphh_cancer_incidence_cohort
    name: Age-adjusted cancer incidence in an assembled KITLG-variant cohort
    description: >-
      Pool molecularly confirmed KITLG gain-of-function carriers across reporting centres and
      compare observed cancer incidence, melanoma in particular, against population rates matched
      for age, sex, and ancestry.
    supporting_outcome:
    - Cancer incidence significantly above matched population rates in variant carriers, which
      would make surveillance a live question.
    refuting_outcome:
    - Incidence indistinguishable from population rates, establishing the reported cancers as
      coincidental and closing the question.
notes: >-
  Scope and lump/split decision. Three MONDO terms sit close together here and they do not all
  mean the same thing, so the identifiers rather than the labels have to drive the call.

  MONDO:0007771 (this entry) carries OMIM:145250 - the KITLG entity. MONDO:0017239, placed as
  its child, carries Orphanet:280628 and no OMIM id; it is the Orphanet view of that same
  KITLG disease rather than a distinct concept, so it is not curated separately.
  MONDO:0013648, by contrast, carries OMIM:614233 and Orphanet:79146, and OMIM:614233 is FPH1
  - the phenotype mapped to 19p13.1-pter in a Chinese family whose causal gene has never been
  found. That is a genetically distinct disease and is recorded here as a differential, not
  folded in.

  Worth flagging for someone with the standing to judge it: MONDO currently asserts
  MONDO:0013648 (the 19p, gene-unknown FPH1) as a parent of MONDO:0007771 (the KITLG entity).
  That is recorded as an observation only - this entry takes no position on the ontology
  modelling.

  One synonym needs a caveat. "Melanosis universalis hereditaria" is used in the FPHH
  literature for this KITLG entity, and is kept here for that reason, but MONDO assigns it as
  an exact synonym of MONDO:0013648 - the FPH1 term this entry treats as a different disease.
  It is therefore not a safe search key for either concept on its own. "Hyperpigmentation,
  familial progressive, 2" (FPH2) is the label that disambiguates cleanly.

  Within the KITLG entity the hyper-only and hyper-plus-hypo presentations are handled as
  phenotype variability rather than as subtypes, on the strength of the shared p.Asn36Ser
  allele and the single mutational hotspot. DUH2 is kept as a differential rather than merged,
  because the KITLG link there is stated as likely rather than demonstrated.

  The recessive, biallelic KITLG auditory-pigmentary disorder is deliberately excluded: it is
  a different direction of effect on the same gene, produces hypomelanosis and sensorineural
  hearing loss, and is a separate entity.
📚

References & Deep Research

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-5[1m] 50 citations 2026-08-28T20:20:07.955680

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:

Entity OMIM Locus/gene Distinguishing feature
FPHH — hyperpigmentation with or without hypopigmentation, familial progressive #145250 KITLG, 12q21.32 Hypopigmented/ash-leaf macules may be present; CALMs, lentigines
FPH1 — hyperpigmentation, familial progressive, 1 #614233 19pter–p13.1, gene unknown Hyperpigmentation only, no hypopigmented component; mapped in a 3-generation Han Chinese family, onset as early as age 5

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

Resource Identifier
MONDO MONDO:0007771 — "hyperpigmentation with or without hypopigmentation, familial progressive" (as used in the existing stub)
OMIM #145250 (FPHH); gene KITLG *184745
Orphanet ORPHA:280628 "Familial progressive hyper- and hypopigmentation"; ORPHA:79146 "Familial progressive hyperpigmentation" (separate concept)
MedGen / UMLS C1840392
GTR condition C1840392 — 42 tests listed for KITLG, 8 clinical tests for this condition
Genomics England PanelApp KITLG — Green on "Pigmentary skin disorders" (panel 559), monoallelic
ICD-10 No specific code; maps under L81.x (other disorders of pigmentation) — no authoritative source found assigning a specific code; treat as uncoded
ICD-11 Best fit EL5x family (disorders of skin pigmentation) — not verified; do not bind without checking

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

Phenotype Type Onset Course Frequency Candidate HPO
Diffuse/blotchy hyperpigmentation Physical manifestation Birth or first weeks Progressive, then plateaus ~100% (definitional) Hyperpigmentation of the skin (HP:0000953); Progressive hyperpigmentation (listed by GTR — ID unverified)
Hypopigmented macules ("ash-leaf", confetti) Physical manifestation Infancy Progressive in number Common but not obligate — the "with or without" in the disease name Hypopigmented skin patches (HP:0001053, verify)
Café-au-lait macules Physical manifestation Birth to childhood Increase in number Frequent; "the most common skin problems present in FPHH patients" besides the dyspigmentation (PMID:33407466) Café-au-lait spot (HP:0000957); Multiple café-au-lait spots (HP:0007565)
Lentigines Physical manifestation Childhood, "gradually appeared and increased in number" (PMID:39152874) Progressive Frequent Multiple lentigines (HP:0001003, verify)
Palmoplantar involvement Physical manifestation With disease Static/progressive Frequent ("frequently on the palms, soles and oral mucosa" — PMID:33407466) but not universal (spared in the family of PMID:29186243) Palmoplantar hyperpigmentation — no confident HPO ID; check
Oral mucosal / conjunctival pigmentation Clinical sign With disease Progressive Variable; prominent in some (PMID:22577587: tongue, palate, gingiva), absent in others Abnormal oral mucosa morphology / oral pigmentation — check
Hypopigmented striae along Blaschko lines Physical manifestation Reported once — Rare (1 case) Blaschko-linear hypopigmentation (a PanelApp phenotype label for KITLG)
Vitiligo Physical manifestation — — Rare — "Vitiligo was found in one family" (PMID:33407466); GTR lists it Vitiligo (HP:0001045, verify)
Hyperkeratosis Clinical sign — — Rare; listed by GTR/HPO Hyperkeratosis (HP:0000962)
Longitudinal melanonychia Clinical sign — — Rare (single case, both thumbs) Melanonychia — check

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

Field Value
Symbol KITLG (KIT ligand; stem cell factor, SCF; mast cell growth factor, MGF; Steel factor)
HGNC hgnc:6343 (lowercase prefix per repo convention)
NCBI Gene 4254
Ensembl ENSG00000049130
UniProt P21583
OMIM *184745
Cytoband 12q21.32 (older papers write 12q21 / 12q21.31-q23.1 / 12q21.12-q22 as linkage intervals)
RefSeq transcripts NM_000899 (variant b, 10 exons, includes exon 6 with the primary proteolytic cleavage site → soluble SCF) and NM_003994 (variant a, 9 exons, exon 6 skipped → predominantly membrane-bound)

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.

cDNA Protein Report PMID
c.98T>C p.Val33Ala Amyere 2011 (FPHH family) 21368769
c.100A>C p.Thr34Pro Amyere 2011 (separate FPHH family) 21368769
c.101C>T p.Thr34Ile recurrent; sporadic Chinese case 33407466
c.104A>T p.Asn35Ile novel, Chinese family 1 (4 generations, 7 affected) 33407466
c.105T>A p.Asn35Lys novel, Chinese pedigree, co-segregating 36453959
c.107A>G p.Asn36Ser the index FPH allele (6-generation Chinese family, LOD 4.35 at D12S81); recurrent — also found in 2 of the 7 Amyere FPHH families 19375057, 21368769
— p.Val37 (residue implicated; specific substitution not stated in accessible text) tabulated by Wang J 2021 33407466
c.113A>C p.Lys38Thr de novo, sporadic 15-year-old Han Chinese boy; extends hotspot to VTNNVK 39152874

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

cDNA Protein Report PMID
c.329A>T p.Asp110Val de novo, Slovenian patient; 3rd α-helix 34716665
c.329A>G p.Asp110Gly de novo; also previously reported as a post-zygotic mosaic variant in a 6-year-old boy with congenital linear and mottled hyperpigmentation 41779177; mosaic case cited in 33407466
c.337G>A p.Glu113Lys novel; "located within another ligand-receptor interaction site" 32189379

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

Disorder OMIM Inheritance Mechanism
FPHH 145250 AD Heterozygous GOF missense, KIT-ligand domain
DFNA69 — nonsyndromic deafness 69, congenital unilateral/asymmetric 616697 AD Heterozygous, e.g. p.Ser96Ter, p.His67_Cys68delinsArg, p.Leu104Val
Waardenburg syndrome type 2F 619947 AR Biallelic; e.g. homozygous c.94C>T p.Arg32Cys
Biallelic hypomelanosis + SNHL — AR Biallelic LOF → generalized hypomelanosis; residual function → WS2/piebaldism-like
Skin/hair/eye pigmentation variation 7 (SHEP7) 611664 complex Common regulatory variation
Testicular germ cell tumour susceptibility 273300 complex rs995030 etc., OR ≈ 2.4–2.6 per risk allele

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

Modality Utility for FPHH
Single-gene KITLG sequencing First-line and usually sufficient. All coding exons + flanking intronic sequence, Sanger or NGS. Exons 2 and 4 carry every reported allele. Method as used by PMID:33407466: "All exons and their flanking intronic sequences of the KITLG gene were amplified by polymerase chain reaction ... sequenced directly using an ABI Prism 3730"
Targeted gene panel Strongly indicated when the differential is broad. KITLG is Green on Genomics England PanelApp "Pigmentary skin disorders" (panel 559), monoallelic. A dyschromatosis/pigmentary panel should also carry ABCB6, SASH1, NF1, SPRED1, PTPN11, TSC1/TSC2, KIT, MITF, SOX10, PAX3, STK11
WES Used successfully for de novo/sporadic cases (PMID:39152874, PMID:41779177, PMID:36453959). Valuable because it simultaneously excludes NF1/SPRED1: "no suspected disease-causing variants in NF1 or SPRED1 leading to similar manifestations were identified in the whole-exome sequencing"
WGS No specific added value demonstrated; reasonable for KITLG-negative families where a novel locus is suspected
Trio testing Important — establishes de novo status and informs recurrence risk
Lesional (skin) DNA testing Under-used and mechanistically important. Digital PCR on DNA from individual lesions detected copy-neutral LOH present only in the hypopigmented macule (PMID:39269165). Blood-only testing will miss both mosaic causal alleles and revertant clones
CMA / karyotype / FISH Not indicated. No CNV or cytogenetic mechanism
mtDNA testing Not indicated
Repeat expansion testing Not indicated

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.

Differential How to distinguish
Neurofibromatosis type 1 CALMs + axillary/inguinal freckling, but no diffuse background hyperpigmentation; Lisch nodules, neurofibromas, optic glioma; NF1 variant
Legius syndrome "characterized by familial café-au-lait spots and skin fold freckling, caused by mutations in SPRED1" (PMID:21368769); no diffuse hyperpigmentation
Dyschromatosis universalis hereditaria (DUH1/2/3) Hyper- and hypopigmented macules but on normal-appearing background skin, not diffuse hyperpigmentation; reticulate; ABCB6 (DUH3) / SASH1. DUH2 maps to 12q21–q23 — overlapping the FPHH locus, and Amyere et al. suggest KITLG may underlie DUH2 too ("mutations in a single gene cause various pigmentation disorders: FPH, FPHH, and likely DUH2")
LEOPARD / Noonan with multiple lentigines Lentigines + cardiac, growth, genital, deafness features; PTPN11
Tuberous sclerosis complex Ash-leaf macules without diffuse hyperpigmentation; angiofibromas, shagreen patch, seizures, tubers
Peutz–Jeghers syndrome Perioral/mucosal lentigines, GI polyposis; STK11
Piebaldism / Waardenburg Congenital stable leukoderma with white forelock; loss-of-function KIT/KITLG/MITF/PAX3/SOX10 — the mechanistic mirror image
Addison disease / Cushing / ACTH-driven Acquired, mucosal + palmar-crease accentuation, abnormal endocrine labs
Carbon baby syndrome (universal acquired melanosis) Acquired diffuse darkening, non-familial
Haemochromatosis, drug-induced (incl. imatinib), heavy metals, smoker's melanosis Acquired, exposure history, distinctive labs
Naegeli–Franceschetti–Jadassohn / dermatopathia pigmentosa reticularis Reticulate pigmentation with nail/dental/sweating abnormalities; KRT14

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:

Intervention Rationale Candidate NCIT (verify) Evidence in FPHH
Photoprotection (broad-spectrum SPF ≥30, physical measures) Limits UV-driven superimposed darkening and PIH after any procedure NCIT:C15747 Supportive Care None. Inference only
Camouflage cosmetics Direct cosmetic benefit, zero risk NCIT:C15747 None
Genetic counselling The single most clearly indicated intervention — AD, 50% recurrence, reduced penetrance, de novo cases NCIT:C15240 Genetic Counseling Standard of care by inference from inheritance
Topical lightening (hydroquinone CHEBI:17594, tretinoin CHEBI:15367, triple-combination cream) Standard for epidermal hyperpigmentation NCIT:C15986 Pharmacotherapy + therapeutic_agent None in FPHH. Also mechanistically dubious here: the drive is a continuous constitutive signal, so any lightening should relapse
Q-switched Nd:YAG laser (1064/532 nm) "The gold standard in managing benign hyperpigmentations is currently 1064/532 nanometers Q-Switched lasers"; 36.4–76.6% success in solar lentigines Laser therapy — no confident NCIT ID; check None in FPHH. Note picosecond laser has been used in SASH1-DUH (Skin Health Dis 2025), the nearest published precedent
Gingival depigmentation For symptomatic oral pigmentation check The one FPHH-specific procedural suggestion (PMID:22577587)
Psychosocial support Visible congenital difference NCIT:C15747 None; inference

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.

Level Applicable? Detail
Primary Only reproductive Genetic counselling (NCIT:C15240) — AD, 50% recurrence per pregnancy from an affected parent, reduced penetrance, documented de novo cases (so unaffected parents of a proband have low but non-zero recurrence risk via possible germline mosaicism). Prenatal diagnosis and PGT-M are technically available once the familial variant is known; whether to offer them for a non-life-limiting cosmetic condition is a family-level values decision
Secondary Limited Cascade testing of at-risk relatives; early dermatologic recognition to avoid a diagnostic odyssey and, importantly, to avoid misdiagnosis as NF1, which would trigger unnecessary NF1 surveillance (imaging, ophthalmology) and cause real anxiety and cost
Tertiary Limited Photoprotection to limit superimposed UV darkening (inferred, not evidenced); careful patient selection before laser/peel to avoid PIH; periodic skin examination — reasonable general practice in a patient with numerous pigmented lesions, and made more reasonable (though not established) by the single family reporting melanoma

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

Gap Kind Why it matters
Mechanism of hypopigmented macule formation KNOWLEDGE_GAP Explicitly stated as unknown by the field; revertant-mosaicism hypothesis rests on one patient
Melanocyte hyperplasia vs per-cell hyperfunction KNOWLEDGE_GAP Primary literature is internally contradictory (PMC2680999)
Increased KITLG–KIT affinity never directly measured KNOWLEDGE_GAP The central mechanistic claim is structural inference, not biophysics
KITLG-negative FPHH families / second locus KNOWLEDGE_GAP Multiple families; FPH1 at 19pter–p13.1 unsolved
No animal model of any FPHH allele HUMAN_MODEL_MISMATCH K14-Scf models the pathway direction but not the allele; Kitlg^Δ/+ models the opposite direction
Penetrance unquantified; no genotype–phenotype correlation KNOWLEDGE_GAP Blocks counselling precision
No prevalence estimate KNOWLEDGE_GAP prevalence_class: ULTRA_RARE with measure_type: UNKNOWN is the honest record
Neurodevelopmental features: entity feature or coincidence? KNOWLEDGE_GAP Two pedigrees report them; the molecularly confirmed series contradicts
Malignancy signal in two families KNOWLEDGE_GAP Unreplicated; must not be curated as an established complication
No QoL data despite a highly visible congenital condition KNOWLEDGE_GAP Attach to clinical_burden#
Isoform (soluble vs membrane-bound) effects untested KNOWLEDGE_GAP All functional work used sKITLG only

Sources

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.

Outcome Count
References checked 29
Resolved 29
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 45
Quoted claims found in source 30
Quoted claims not found in source 15
Quoted claims with nothing to check against 1
References weighed for topical relevance 29
On topic 15
Off topic 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.

Outcome Count
Terms checked 43
Resolved 38
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 3
Terms whose name was checked 6
Terms named correctly 5
Terms named as a different term 1

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.