Congenital Alopecia Syndromes with Systemic Involvement (GAPO, MBTPS2 Spectrum, SREBF1 Spectrum, APMR and FOXN1 Deficiency)

A class of rare monogenic disorders in which absence or early loss of scalp hair, eyebrows and eyelashes is associated with ocular, cutaneous, dental, skeletal, neurological or immune involvement: GAPO syndrome (ANTXR1, autosomal recessive), disorders of the SREBP pathway — X-linked MBTPS2 and autosomal dominant SREBF1 —, alopecia–intellectual disability syndrome (AHSG, LSS, loci without an identified gene, and ITGB6) and FOXN1 deficiency (recessive "nude" athymia, and dominant T-cell lymphopenia due to haploinsufficiency); Olmsted syndrome, whose X-linked form belongs to the MBTPS2 spectrum, is covered in all its forms (TRPV3 and PERP, autosomal).

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

The table brings together the entities covered in this article. None has a dedicated GeneReviews® text: the existing mentions are in the chapters on non-syndromic tooth agenesis (ANTXR1), COL1A1/COL1A2 osteogenesis imperfecta (MBTPS2), tyrosinaemia type II (MBTPS2/Olmsted in the differential diagnosis) and X-linked severe combined immunodeficiency (SCID) (FOXN1 among the causes of a SCID-like phenotype) [1–4]. Orphanet prevalences are classes (<1/1 000 000) accompanied by the number of published cases, not population estimates [5–8]. The last column gives the relevant European Reference Networks (ERNs).

1. Introduction

1.1. A class defined by syndromic congenital alopecia

Absence of hair at birth, or its loss in the first months of life, is in most families an isolated disorder of the hair follicle, belonging to the group of congenital and hereditary alopecias. A minority of children have, in addition to alopecia, involvement of other tissues derived from ectoderm or mesenchyme — teeth that fail to erupt, cornea, lens, skin, thymus, nervous system or bone —, and it is this involvement that determines the prognosis. This article brings together five groups of monogenic disorders in which congenital or early alopecia is a cardinal sign and the picture is systemic: GAPO syndrome, caused by biallelic loss of function of ANTXR1; the X-linked MBTPS2 spectrum, which ranges from the IFAP triad (ichthyosis follicularis, atrichia and photophobia) to BRESHECK syndrome, keratosis follicularis spinulosa decalvans (KFSD), Olmsted syndrome and osteogenesis imperfecta type XIX; the autosomal dominant SREBF1 spectrum (IFAP2 and hereditary mucoepithelial dysplasia); alopecia–intellectual disability syndrome (APMR, alopecia–mental retardation), with four numbered types in OMIM; and FOXN1 deficiency, the human homologue of the "nude" mouse, which combines congenital alopecia universalis, nail dystrophy and athymia [14, 20, 51, 60, 66]. Reference textbooks deal with these entities in different contexts — ectodermal dysplasias, disorders of isoprenoid and cholesterol synthesis, combined immunodeficiencies, and the approach to the patient with unusual hair, teeth, nails and skin —, and the classification that follows groups them by the sign that brings them together at the first consultation [14, 75–77].

1.2. GAPO syndrome

The first patient was described in Denmark in 1947 (Andersen and colleagues), and the acronym GAPO — growth retardation, alopecia, pseudoanodontia and optic atrophy — was proposed by Tipton and Gorlin in 1984 [14]. Because optic atrophy occurs in only about one third of patients, Smith's Recognizable Patterns considers "ocular manifestations" a more accurate expression for the last letter [14]. By 2013 more than 30 cases of various origins had been described, most of them children of consanguineous parents; histopathology showed abnormal accumulation of extracellular material, with no identifiable biochemical or endocrine abnormality [78]. In 2013, Stránecký and colleagues identified biallelic loss-of-function variants in ANTXR1, which encodes anthrax toxin receptor 1, in four patients from Czech, Egyptian and Sinhalese families [78]. The review by Modafferi and colleagues, published online in 2025, gathered 105 cases described since 1947 and confirmed the multisystem nature of the disease, with predominantly skeletal, dermatological and ophthalmological involvement [13].

1.3. The MBTPS2 spectrum: IFAP, BRESHECK, KFSD, Olmsted syndrome and osteogenesis imperfecta XIX

The association of ichthyosis follicularis, atrichia and photophobia was described as a syndrome by MacLeod in 1909, in three boys [20]. KFSD was described by Siemens in 1925, in two families with X-linked transmission, one Bavarian and the other Dutch, whose patients had previously been published as cases of ichthyosis follicularis [25]. In 1997, Reish and colleagues used the acronym BRESEK for the common findings (brain anomalies, intellectual disability, ectodermal dysplasia, skeletal deformities, ear or eye anomalies and kidney dysplasia) and BRESHECK for the complete picture, which adds Hirschsprung disease and cleft palate or cryptorchidism, in two maternal half-brothers [17]. Oeffner and colleagues mapped the IFAP locus to Xp22.11–p22.13 and, in 2009, identified missense variants in MBTPS2, which encodes site-2 protease (S2P) [79]. In 2010, Aten and colleagues showed that X-linked KFSD is caused by the same protein, with the variant NM_015884.4:c.1523A>G p.(Asn508Ser) in Siemens' large Dutch family and in British and American families, and proposed that IFAP and KFSD form a spectrum [28]. X-linked Olmsted syndrome followed, in an Iranian family, together with X-linked recessive osteogenesis imperfecta (type XIX), described by Lindert and colleagues in 2016 in Thai and German families without dermatological signs [32, 50].

Olmsted syndrome was described in 1927 in an Italian-American boy with painful palmoplantar keratoderma, deep fissures, pseudoainhum (digital constriction bands), curved and thickened nails and fissured periorificial hyperkeratosis [46]. For 85 years the diagnosis was purely clinical; in 2012, Lin and colleagues identified, by trio exome sequencing, gain-of-function missense variants of TRPV3 in six Chinese patients, the X-linked form due to MBTPS2 was published the following year in an Iranian family (uncle and nephew), and in 2019 heterozygous truncating variants of PERP, a desmosomal component, were recognised as a third cause [39, 42, 80]. OMIM separates Olmsted syndrome 1 (TRPV3, 614594), Olmsted syndrome 2 (PERP, 619208) and the X-linked form (300918), whereas Orphanet groups them into a single entity, mutilating palmoplantar keratoderma with periorificial keratotic plaques (ORPHA:659) [33, 35, 36]. Wilson and colleagues extended the TRPV3 phenotype to painful focal plantar keratoderma without periorificial plaques and proposed that painful keratodermas caused by other genes should not be called Olmsted syndrome [46].

1.4. The SREBF1 spectrum: IFAP2 and hereditary mucoepithelial dysplasia

Hereditary mucoepithelial dysplasia (HMD) was described by Witkop and colleagues in 1979, in a four-generation family with flat red lesions of the periorificial mucosae, follicular keratosis, photophobia and nystagmus in childhood, keratitis, pannus and cataract, and non-scarring alopecia [52]. In 2020, two groups linked dominant phenotypes to SREBF1: Wang and colleagues, in 11 patients with autosomal dominant IFAP (IFAP2), and Morice-Picard and colleagues, in patients with HMD [55, 81]. Comparison of series later showed that the two designations correspond to a clinical spectrum; in 2026, Slater and colleagues applied the ClinGen criteria for lumping or splitting entities and proposed a single disorder, "SREBF1-syndromic epidermal differentiation disorder" (SREBF1-sEDD) [53, 82, 83]. Normalisation of the variants shows the molecular basis of this overlap: the "p.Arg557Cys" described in HMD using the numbering of transcript NM_001005291.3 is the same genomic change as the "p.Arg527Cys" of IFAP2 in the MANE transcript NM_004176.5 (c.1579C>T) [10, 53]. In 2024 a third entity of the same gene was described, with the opposite mechanism: generalised hyperpigmentation and congenital cataract due to a truncating gain-of-function variant [84].

1.5. Alopecia–intellectual disability syndrome (APMR)

Perniola and colleagues described in 1980 two siblings, children of consanguineous parents, with congenital alopecia, psychomotor delay, seizures and deafness, and Baraitser and colleagues described in 1983 three cousins from a consanguineous Middle Eastern family with total alopecia and severe intellectual disability [60]. Orphanet uses the eponym Perniola-Krajewska-Carnevale as a synonym and describes the syndrome in fewer than 20 families [7]. Linkage studies in Pakistani families defined three recessive loci — 3q26.33–q27.3 (APMR1), 3q26.2–q26.31 (APMR2) and 18q11.2–q12.2 (APMR3) —, and in 2017 a homozygous variant in AHSG was associated with APMR1 in an Iranian family, a relationship that OMIM keeps as provisional [60–62, 85]. In 2019, Besnard and colleagues showed that biallelic variants in LSS, the lanosterol synthase gene already linked to congenital cataract and hypotrichosis simplex, cause a recessive neuroectodermal syndrome that OMIM numbered APMR4 [63, 65]. A Pakistani family with adolescent-onset alopecia, intellectual disability and dentogingival anomalies due to a homozygous variant in ITGB6 explains the inclusion of this gene in the Orphanet entry [7, 64].

1.6. FOXN1 deficiency

Pignata and colleagues described in 1996 two sisters from a village in southern Italy (Acerno) with congenital alopecia, severe T-cell immunodeficiency and dystrophy of all nails; Frank and colleagues identified in 1999 the homozygous nonsense variant p.(Arg255*) in FOXN1 and recognised the phenotype as the human homologue of the "nude" mouse [66]. The gene encodes a forkhead/winged helix transcription factor that is the master regulator of the thymic epithelium and takes part in the differentiation of keratinocytes and the hair follicle [9, 86]. In 2019, Bosticardo and colleagues showed that haploinsufficiency causes a distinct dominant entity, detected by newborn screening for T-cell lymphopenia: infantile T-cell lymphopenia with or without nail dystrophy [72, 74]. Treatment of biallelic deficiency changed with allogeneic thymus tissue implantation, approved in the United States in 2021 [87].

1.7. Operational definitions

For the purposes of this article, GAPO syndrome is defined by the combination of pseudoanodontia (formed, retained teeth that fail to erupt), progressive alopecia, postnatal growth retardation and characteristic craniofacial features, confirmed by biallelic variants in ANTXR1 [9, 78]. IFAP1 is defined in boys by the triad of ichthyosis follicularis, congenital non-scarring atrichia and photophobia, with a hemizygous variant in MBTPS2; BRESHECK is IFAP1 with cerebral, skeletal, intestinal and renal malformations [17, 20]. KFSD is defined by follicular hyperkeratosis with progressive scarring alopecia of the scalp, eyebrows and eyelashes, with or without photophobia [26, 27]. IFAP2/HMD is defined by non-scarring alopecia, follicular keratosis and ocular surface disease with a heterozygous variant in SREBF1 [51, 52]. APMR is defined by congenital total alopecia and intellectual disability with recessive inheritance [60]. FOXN1 deficiency is defined, in the biallelic form, by congenital athymia with a T−B+NK+ phenotype, alopecia universalis and nail dystrophy, and in the heterozygous form by T-cell lymphopenia with low TRECs (T-cell receptor excision circles) on newborn screening [66, 72].

2. Molecular Genetics and Pathophysiology

2.1. Genetic classification of the class

The following table brings together all the types with their own OMIM number, ordered by gene, with the features that distinguish them and the test that discriminates them. Autosomal dominant KFSD and the APMR2 and APMR3 loci have no identified gene; OMIM entry 620690, which some lists associate with KFSD through LRP1, corresponds to developmental dysplasia of the hip type 3, and the link between LRP1 and the scarring follicular keratoses comes from keratosis pilaris atrophicans (OMIM 604093), of which KFSD is a clinical subtype [26, 30, 88, 89].

2.2. ANTXR1 and extracellular matrix homeostasis

ANTXR1 (2p13.3; synonyms TEM8 and ATR) encodes a type I transmembrane protein that binds extracellular matrix proteins, mediates adhesion to type 1 collagen and gelatin, links the matrix to the actin cytoskeleton, promotes cell spreading and migration and takes part in the endothelial angiogenic response; it was identified as a tumour endothelial marker and as the receptor for the protective antigen of anthrax toxin [9, 78]. GAPO syndrome results from biallelic loss of function. In the founding article, the nonsense variants NM_032208.3:c.262C>T p.(Arg88*) — found in two Egyptian families, on distinct haplotypes and at a CpG dinucleotide, which suggests recurrent mutation — and c.505C>T p.(Arg169*) triggered nonsense-mediated messenger RNA decay (NMD) and absence of the protein in fibroblasts, and the splicing variant c.1435-12A>G would produce a truncated protein with a C-terminal neopeptide of 118 amino acids [10, 78]. By 2024, 15 pathogenic variants had been described, with no common variant and no hotspot; they include frameshift and splicing variants, the missense variants c.1150G>A p.(Gly384Ser), p.(Gln137Leu), p.(Cys317Arg) and p.(Glu222Lys) in the extracellular domain, and a large intragenic deletion of exon 3 [16, 94, 95]. In a six-year-old Indian boy, the homozygous missense variant NM_032208.3:c.265G>A p.(Gly89Arg), in exon 3, was described, with the relatives tested being heterozygous [10, 96]. In a consanguineous Indian family with three affected sisters, the homozygous variant was NM_032208.3:c.572T>C p.(Ile191Thr); the two sisters with congenital glaucoma also shared a rare heterozygous TGFBI variant, NM_000358.3:c.968C>T p.(Ala323Val), likely benign by the criteria of the American College of Medical Genetics and Genomics (ACMG), which the authors propose as a possible modifier, without functional demonstration [10, 97]. A case described in 2019 showed homozygosity due to uniparental disomy of chromosome 2, in which only one parent is a carrier [98].

The common pathology is excessive deposition of extracellular matrix with fibrosis. Skin biopsies show epidermal atrophy, hyaline material in the upper dermis and atrophy of the hair follicles; fibroblasts have disorganised cytoskeletal microfilaments and accumulate matrix [14]. The same hyalinisation has been found in Tenon's capsule, in the ovaries (with parenchymal atrophy and follicular depletion) and, at autopsy, as interstitial fibrosis and coronary and cerebral atherosclerosis [14, 99, 100]. At the autopsy of a Brazilian patient there was accumulation of extracellular material in several tissues, and Wajntal and colleagues proposed in 1990 the designation "GAPO dysplasia", attributing the disease to a failure of degradation of matrix components [101]. Electron microscopy of the gingiva of an Egyptian child showed an excess of collagen fibres and endothelial vacuolisation [102]; by contrast, thigh and scalp biopsies from a five-year-old Indian girl had no PAS-positive hyaline material, so dermal hyalinisation is not constant [103]. Mice with Antxr1 disruption reproduce the excess of matrix in the ovaries, uterus, skin, hair follicles, cranial sutures and periodontal ligament, with dental dysplasia, and the females are infertile [78]. In Antxr1-null mice, loss of the protein in endothelial cells reduces basement membrane synthesis and activates vascular endothelial growth factor (VEGF) receptor signalling, with hyperproliferative and leaky cutaneous vessels; in fibroblasts the synthesis of fibrillar collagens increases, with progressive fibrosis of the skin and other organs, and the altered interaction between the two cell types reduces the activity of the metalloproteinase MMP2 [104]. In primary fibroblasts from these mice, the increase in type I collagen and fibronectin depends mainly on connective tissue growth factor (CTGF), through a cell-autonomous mechanism, and partly on VEGF [105]. Pigs with ANTXR1 disruption by genome editing show a GAPO-like phenotype, both with the null allele and with an in-frame deletion, and are resistant to infection by Senecavirus A, which uses ANTXR1 as its receptor [106]. The analogy with juvenile hyaline fibromatosis and infantile systemic hyalinosis, caused by the homologue ANTXR2, was highlighted in the original description [78]. In 2024, Przyklenk and colleagues showed that loss of ANTXR1 induces senescence in human fibroblasts — the WI-26 line with a CRISPR knockout and fibroblasts from two patients —, with changes in nuclear architecture and actin dynamics, without changes in the components of the LINC complex or in prelamin A, and proposed reconsidering GAPO as a progeroid disorder; this is a mechanistic proposal, with no change in classification [107]. A hypomorphic homozygous variant, NM_032208.3:c.1312C>T p.(Arg438Cys), was found in a Turkish family with isolated tooth agenesis, without features of GAPO, and the GeneReviews chapter on non-syndromic tooth agenesis considers the association data preliminary [1, 10, 90]. Heterozygous missense variants of ANTXR1 have been associated with infantile haemangioma, and some patients with GAPO have haemangiomas [78].

2.3. The SREBP pathway: MBTPS2 and SREBF1

Sterol regulatory element-binding proteins (SREBPs) are transcription factors synthesised as precursors inserted in the endoplasmic reticulum membrane. When cellular sterols fall, they are transported to the Golgi apparatus and cleaved sequentially by site-1 protease (S1P) and site-2 protease (S2P, encoded by MBTPS2); the released N-terminal domain enters the nucleus and activates genes for cholesterol and fatty acid synthesis and the LDL receptor [9, 75]. S2P is an intramembrane zinc metalloprotease that makes the second cut of this regulated intramembrane proteolysis also in ATF6, ATF6B and OASIS (CREB3L1), factors of the endoplasmic reticulum stress response and of bone formation [9, 50]. Saudubray includes IFAP in the chapter on disorders of isoprenoid and cholesterol synthesis and stresses that, with MBTPS2 variants, the serum lipid profile is unchanged: the defect lies in cell signalling, and SREBF1 variants reduce the transcription of genes for cholesterol synthesis and keratins [75].

2.3.1. MBTPS2

MBTPS2 (Xp22.12) has 11 exons, and the long isoform has 519 amino acids and eight transmembrane domains [21, 108]. Only missense variants and intronic variants that alter splicing have been described; the hypothesis is that male embryos do not tolerate complete loss of function, and male mice hemizygous for the knockout or for an OI variant die in the embryonic period [21, 109]. The reference functional assay is complementation of protease-deficient M19 hamster cells: the normal protein restores induction of an SRE-regulated reporter gene and growth in medium without cholesterol or lipids, and the patients' variants do so partially; in males, the degree of loss of activity correlates with clinical severity [79]. The variant NM_015884.4:c.1523A>G p.(Asn508Ser) halves the response to sterols [10, 28].

Bornholdt and colleagues studied 11 missense variants in 13 families: the substitutions cluster in the transmembrane domains, those near the active site are the most deleterious and are associated with the most severe phenotypes, and in males a correlation between variant position and phenotype (IFAP with or without BRESHECK, KFSD-X or Olmsted syndrome) begins to emerge [110]. The compilation of 32 variants published by Strong and colleagues makes this distribution by domain visible, as summarised in the table [108, 111]. In an 11-year-old Chinese boy with diffuse follicular hyperkeratosis, alopecia and photophobia, the variant was NM_015884.4:c.1298T>C p.(Leu433Pro), hemizygous [10, 112].

The correlation has limits. The same p.(Asn508Ser) causes KFSD in Dutch, British and American families and IFAP in a Chinese family; p.(Arg429His) caused severe BRESHECK in a German family and a milder picture in a Japanese patient; and the intronic variant c.970+5G>A, found in families from Pakistan, China and Argentina on distinct haplotypes — a mutational hotspot rather than a founder effect —, produced oculocutaneous severity in all of them, but neurodevelopmental impairment and absence seizures only in the Argentinian patient [20, 113–115]. These data point to genetic, epigenetic or environmental modifiers [114]. The IFAP/Olmsted overlap may have a partial molecular basis: S2P regulates the regulatory region of TRPV3, the main gene of autosomal Olmsted syndrome [116].

In heterozygous women, expression depends on X-chromosome inactivation. In symptomatic KFSD carriers, skewed inactivation of the normal allele parallels severity; in IFAP, the mother and sister of an affected boy had linear scaling, atrophoderma, hairless patches and linear hypohidrosis following Blaschko's lines [9, 28]. In OI XIX, the mother of the Thai proband was healthy and had normal bone mineral density, and the mother of the German proband had non-skewed X inactivation (0.70) [49, 50].

OI XIX illustrates that the same proteolysis defect produces non-overlapping phenotypes. The variants NM_015884.4:c.1376A>G p.(Asn459Ser) and c.1515G>C p.(Leu505Phe) reduce cleavage of OASIS, ATF6 and SREBP, decrease type I collagen secretion and hydroxylation of lysine K87, which is critical for cross-linking (43% versus 90% in the control in the α1(I) chain and 7% versus 43% in α2(I)), and impair osteoblastic differentiation; the patients have no signs of IFAP or KFSD [10, 50]. Models using induced pluripotent stem cells differentiated into osteoblasts show mechanisms distinct from those of type I collagen OI [117].

2.3.2. SREBF1

SREBF1 (17p11.2, within the Smith-Magenis syndrome region) encodes SREBP-1 [9]. IFAP2 and HMD variants cluster around the S1P cleavage site: substitution or deletion of residues 527, 528 and 530 in the MANE transcript NM_004176.5 [55]. In the assays of Wang and colleagues, these proteins were not cleaved by S1P, did not enter the nucleus and had reduced transcriptional activity; the patients' scalp skin showed a marked reduction of LDLR transcripts and of outer root sheath keratins, and increased keratinocyte apoptosis [55]. The most frequent variant, NM_004176.5:c.1579C>T p.(Arg527Cys), was found in 10 unrelated patients of Chinese, German, Congolese, Italian, African American and Indian origin, de novo in four of the sporadic cases [51]. The variants described in HMD as the "p.Arg557 hotspot" use the numbering of transcript NM_001005291.3 (SREBP-1a isoform): NM_001005291.3:c.1669C>T p.(Arg557Cys) and c.1670G>A p.(Arg557His) correspond to the same genomic positions as NM_004176.5:c.1579C>T p.(Arg527Cys) and c.1580G>A p.(Arg527His) [10, 81]. Two diagnoses with the same variant explain the conclusion of Slater and colleagues, which favours a single entity [53]. Other variants are p.(Asn528del) (c.1582_1584del) and p.(Leu530Pro) [10, 51].

The opposite mechanism was described in 2024: the de novo nonsense variant NM_004176.5:c.1289C>A p.(Ser430*) produces a truncated protein, preferentially nuclear and with increased transcriptional activity (gain of function); the patients' melanocytes synthesised more melanin, and the phenotype is generalised hyperpigmentation with xerosis and congenital cataract, without alopecia as a cardinal sign [10, 84]. In the meibum of a patient with p.(Arg527Cys), mass spectrometry showed an excess of saturated wax esters, with a higher melting point, which explains the poor expressibility of the secretions and meibomian gland dysfunction [118].

2.4. APMR genes: AHSG, LSS and ITGB6

In APMR1, the homozygous variant NM_001622.4:c.950G>A p.(Arg317His) in AHSG (fetuin-A) segregated in seven affected members of a consanguineous Iranian family; it lies in a phosphorylation motif of the propeptide, and the serum protein of homozygotes was of altered size [10, 85]. OMIM keeps the "?" symbol, because only one family has been described [60]. APMR2 and APMR3 remain defined only by linkage, with no identified gene; in APMR3, nine candidate genes in the interval were sequenced without result [61, 62].

LSS (21q22.3) encodes the endoplasmic reticulum enzyme lanosterol synthase (oxidosqualene cyclase), which cyclises (S)-2,3-oxidosqualene to lanosterol, the first sterol-specific step in the synthesis of cholesterol, steroid hormones and vitamin D; lanosterol is abundant in the lens [9, 119]. Biallelic variants cause a recessive spectrum: congenital cataract (type 44), hypotrichosis simplex (type 14), APMR4 and palmoplantar keratoderma with congenital alopecia type 2 (PPKCA2) [63, 91–93]. In 2018, Romano and colleagues proposed that N-terminal variants cause hair loss and C-terminal variants cataract; a review of 29 families in 2023 confirmed an emerging correlation, with exceptions such as the child with cataract and hypotrichosis due to p.(Ile342Ser)/p.(Trp629Cys) (published designation; MANE transcript NM_002340.6) [91, 92, 120]. The mutant proteins localise partly outside the endoplasmic reticulum, and plasma cholesterol and its precursors are generally normal [65, 121]. Mice with an epidermal Lss knockout die of neonatal dehydration (skin barrier), the knockout induced in adulthood causes hypotrichosis, and the lens knockout causes cataract [122]. In APMR4, the variants described include truncating, missense and splicing variants, with transcript and minigene studies confirming the effect of the intronic ones [65, 120].

ITGB6 encodes the β6 integrin subunit, associated with amelogenesis imperfecta; the homozygous variant NM_000888.5:c.898G>A p.(Glu300Lys), in the β-propeller domain, segregated with intellectual disability, adolescent-onset alopecia and dentogingival anomalies in a Pakistani family [10, 64].

2.5. FOXN1 and thymic development

FOXN1 (17q11.2) encodes a forkhead/winged helix transcription factor that directs development of the thymic epithelium from the initial progenitor to maturation of the cortical and medullary epithelium, the microstructure and the vascularisation of the thymus; in keratinocytes and the hair follicle it promotes terminal differentiation [9, 86]. The defect lies in the thymic stroma and not in the haematopoietic progenitors, which explains why haematopoietic stem cell transplantation is not curative whereas thymus tissue implantation is [9, 66].

The effect is gene-dosage dependent. Biallelic variants cause athymia; the founder variant NM_001369369.1:c.763C>T p.(Arg255*) (c.763C>T also in transcript NM_003593.3) was found in the Acerno families and, in the homozygous state, in patients of Portuguese and Indian origin, and c.958C>T p.(Arg320Trp) in a child of French–North African parents [10, 66, 70]. A fetus homozygous for p.(Arg255*) had no thymus and had a complete block of CD4+ maturation with scant non-functional CD8+ cells, which indicates some FOXN1-independent lymphopoiesis [66]. Heterozygous loss-of-function variants — mostly nonsense, frameshift or splicing variants, with transcriptional activity between 2% and 95% of normal (most below 20%) — cause neonatal T-cell lymphopenia with low TRECs; in nu/+ mice, early thymic progenitors are reduced until three to five weeks and FOXN1 target genes (Ccl25, Cxcl12, Psmb11, Cd83, Dll4) show reduced expression, with delayed medullary maturation [72, 74]. More than 400 FOXN1 variants have been described; functional assays classify them as benign, loss-of-function or gain-of-function, or dominant-negative — the latter in frameshift variants of the transactivation domain —, and most remain classified as variants of uncertain significance (VUS) [123, 124]. In a Belarusian family, the heterozygous variant p.(Pro465Argfs*82) was associated with a SCID-like phenotype in four carriers, which suggests a dominant-negative effect [70]. Penetrance of the dominant form is incomplete [72].

2.6. TRPV3 and PERP: autosomal Olmsted syndrome

TRPV3 (17p13.2) encodes transient receptor potential vanilloid 3, a homotetrameric non-selective cation channel, with six transmembrane helices (S1–S6) per subunit and a conserved C-terminal TRP domain, activated by temperatures between 31 and 39 °C and by ligands such as camphor, carvacrol and 2-aminoethoxydiphenyl borate; it is expressed mainly in keratinocytes of the basal layer and of the outer root sheath of the follicle, in sensory neurons and in the central nervous system [43, 44]. Olmsted syndrome variants are gain-of-function: in transfected HEK293 cells, the mutant channels generate much larger inward currents, through constitutive opening, with calcium overload and keratinocyte apoptosis [39]. TRPV3 forms a signalling complex with TGF-α and the epidermal growth factor receptor (EGFR), and its excessive activation transactivates EGFR and the PI3K/AKT/mTOR cascade, which links epidermal hyperproliferation to treatment with EGFR and mTOR inhibitors; in the lesional skin of two patients, immunostaining showed increased phosphorylated ribosomal protein S6 and phosphorylated EGFR [44, 48]. Channel activation releases interleukin 1α, prostaglandin E2 and pruritus mediators (thymic stromal lymphopoietin, nerve growth factor, interleukin 33), and expression in nociceptive neurons explains the neuropathic-type pain [43, 44]. A female patient with p.(Gly573Ala) had frequent skin infections, an inflammatory infiltrate, raised IgE, persistent eosinophilia and increased T follicular helper cells [125]. The Trpv3 p.(Gly568Val) mouse model reproduces the epidermal hyperplasia and alopecia, through premature differentiation of follicular keratinocytes and miniaturisation of regenerated follicles [44]. Structural studies from 2026 (cryo-electron microscopy and single-channel recordings of five mutants) showed reduced temperature sensitivity in the physiological skin range and destabilisation of non-conducting states, with different distributions of closed, open and inactivated states depending on the variant [126].

By 2021 at least 22 TRPV3 variants had been described in Olmsted syndrome [44, 127]. Codons 573 and 692 are recurrent: NM_145068.4:c.1717G>A p.(Gly573Ser) had been found in five unrelated patients by 2015, and c.1717G>T p.(Gly573Cys) and c.1718G>C p.(Gly573Ala) have been described at the same codon; at codon 692, c.2074T>G p.(Trp692Gly) and p.(Trp692Cys) [10, 43, 125]. In Zhong's series of nine patients, variants of the S4–S5 linker and of the TRP domain increased basal open probability and voltage sensitivity more and were associated with severe phenotypes, whereas the others had smaller effects: p.(Arg416Gln) corresponded to mild disease, p.(Leu673Phe) to intermediate disease and p.(Trp692Ser) to severe disease, with proportional in vitro cytotoxicity [44, 127]. The variants p.(Gln580Pro) and p.(Met672Ile) are associated with focal keratoderma, and at codon 568 the variants c.1703G>T p.(Gly568Val) and c.1703G>A p.(Gly568Asp) were found in patients with painful focal plantar keratoderma without periorificial plaques [10, 44, 46]. The same p.(Gly568Val) caused severe disease in Asian patients, focal keratoderma in a Brazilian girl and a picture with erythromelalgia in a Brazilian boy, which limits prediction from the variant [45, 46]. Recessive inheritance is documented: homozygosity for p.(Trp521Ser) in a patient described in Israel, and compound heterozygosity for p.(Gly568Cys) and c.784+1G>A (exon skipping with p.(Gln216_Gly262del) at the RNA level) in two siblings with erythromelalgia, whose father, heterozygous for p.(Gly568Cys), was unaffected [40, 46, 128]. In 2024, two compound heterozygous patients were described in whom all four variants (p.(Trp521Cys) with p.(Ser459Leu), and p.(Leu591Phe) with p.(Arg729Gln)) had individual gain of function and a cumulative effect, and the authors proposed ligand-dependent activity assays to classify the variants [129]. Semidominant inheritance has also been described [41]. TRPV3 also has a provisional ("?") association in OMIM with non-epidermolytic focal palmoplantar keratoderma 2 (616400), described in one family [37].

PERP (6q23.3) encodes a p53/p63 effector that is a component of desmosomes [38, 42]. Olmsted syndrome 2 variants are heterozygous nonsense variants in the last exon — NM_022121.5:c.452G>A and c.453G>A p.(Trp151*) and c.459C>G p.(Tyr153*) — and give rise to a truncated protein, expressed in keratinocytes, that appears to be incorporated unstably into desmosomes; these lack the electron-dense midline and intercellular adhesion fails under mechanical stress, without the increased apoptosis seen in the TRPV3 forms [10, 42]. The mechanism is not haploinsufficiency, because the heterozygous parents of an N-terminal frameshift variant, p.(Ser38Leufs52), were unaffected; in the homozygous state, this variant causes erythrokeratodermia variabilis et progressiva 7 (619209, AR) [38, 42]. The same p.(Tyr153), through c.459C>A, was found in a Chinese patient with congenital hypotrichosis, atopic dermatitis and growth retardation, and a heterozygous PERP variant has been described with alopecia universalis [10, 130, 131].

There is no evident clinical difference between Olmsted syndrome due to TRPV3 and the MBTPS2 form, and the clinical variability between patients with the same variant, even within a family, suggests modifier genes or environmental factors; some patients have no variant in any known gene [43].

3. Clinical Spectrum and Manifestations by System

3.1. GAPO syndrome

3.1.1. Evolution with age

Most patients appear normal at birth; length may be slightly reduced, and the changes become progressive from six months, with hair loss, skin laxity and, in some, optic atrophy [14]. Postnatal growth failure is evident between six and twelve months and bone age is delayed [14]. Hair decreases from two to three months and alopecia is total by two to three years, with sparse eyelashes and eyebrows and variable body and facial hair; in an Egyptian series of seven patients, one did not have total alopecia at two years [14, 16]. An Indian child aged 3.75 years had features of prenatal onset, sagittal craniosynostosis with scaphocephaly and bilateral choroid plexus cysts [15]. Facial features change with age, and the skin thickens progressively with an aged appearance [14, 98]. In a Turkish family, two siblings and a cousin had some body hair, white eyelashes, deep grooves on the sternum and back and an athletic appearance, attributed to the excess of connective tissue [132].

3.1.2. Manifestations by system

The face is characterised by frontal bossing, a high and broad forehead, a prominent occiput, a large anterior fontanelle with delayed closure, prominent scalp veins, periorbital oedema, sagging forehead skin, a flat nasal bridge, midface hypoplasia, thick and anteverted nares, a long philtrum, thick lips, large ears and micrognathia [14]. In the founding series of four boys (3 to 18 years), stature was between −2 and −4 standard deviations, head circumference between −2 and +2 standard deviations, and all had frontal bossing, a large and persistent anterior fontanelle, hypertelorism, a depressed nasal bridge, a long philtrum, micrognathia, pseudoanodontia and alopecia [78].

The dental sign defines the syndrome: the deciduous and permanent dentitions form but do not erupt (pseudoanodontia), and the alveolar ridge is thick because it contains both dentitions [14, 133]. The orthopantomogram of two Egyptian siblings showed absence of the lower second premolars, obliteration of the pulp chamber of the first molars and taurodontism; eruption stopped regardless of root length, and a missense variant was associated with normal eruption of the deciduous teeth [94]. Dental retention was attributed to ankylosis [94]. In a family with four affected members there was osteomyelitis of the mandible [134]. In a young Brazilian adult woman, the unerupted deciduous and permanent dentitions simulated total anodontia on clinical examination [135].

Ocular manifestations include progressive optic atrophy (in about one third), cataract, exophthalmos, keratoconus, keratopathy, glaucoma and horizontal nystagmus [14]. In the Egyptian series of seven patients, all had optic atrophy and glaucoma and one had keratopathy [16]. In the founding series, three of three examined had megalocornea, three of four engorged and tortuous retinal vessels and three of four bilateral optic atrophy [78]. Two siblings with craniosynostosis had papilloedema and V-pattern strabismus, and the Tenon's capsule found at surgery was inelastic, highly vascularised and hyalinised [99]. In a 27-year-old Syrian man, peripheral congenital cataract and myelinated nerve fibre layer were described [136]. Optic atrophy is not constant: in a 1999 review it was present in one of four Turkish patients and in five earlier cases, and glaucoma in five cases, with secondary buphthalmos and keratopathy [137]. Congenital glaucoma, bilateral glaucoma in a 36-year-old Brazilian woman and, in two Brazilian siblings, glaucoma and keratoconus without optic atrophy have been described [101, 138, 139]. In four Turkish children from two families, two had bilateral end-stage glaucoma with unilateral corneal opacity and two had myelinated nerve fibre layer, one with bilateral optic atrophy and the other with persistent pupillary membrane [140]. Bilateral interstitial keratitis associated with hypothyroidism has also been described [141]. In a 3.5-year-old Japanese boy with bilateral papilloedema, dilated scalp veins and an intracranial bruit, angiography showed narrowing of the sigmoid sinuses with no flow to the jugular veins, and the authors related the optic atrophy to the intracranial vascular changes [142]. In a 1990 review, optic atrophy was reported in about 30% of patients and was attributed mainly to raised intraocular pressure [143]. In an Indian family, two of three sisters had bilateral congenital glaucoma and the eldest, at ten years, did not have glaucoma [97].

The nervous system and skull frequently show developmental delay and borderline intelligence quotient, mild intellectual disability, occasional microcephaly and craniosynostosis, an abnormal electroencephalogram and changes in the cerebral circulation (arterial tortuosity, dilatation of the basilar and vertebral arteries, venous sinus occlusion) [14]. Multisutural or pansutural craniosynostosis may cause operable intracranial hypertension; at surgery, pericranial and dural adhesions and venous bleeding were unusual [99, 144, 145]. Vestibular dysfunction and hearing loss have been described and, in an adult, external auditory canal stenosis with conductive hearing loss, total aplasia of the paranasal sinuses and mastoid air cells, and a difficult airway [136, 146]. Deafness was described in an Indian child, though a chance association could not be excluded [147]. In a 12-year-old Tunisian boy with pulsatile masses at the vertex and mastoid region and an audible bruit, magnetic resonance imaging, MR angiography and angiography showed very prominent cortical veins, hypoplasia of the left transverse sinus and agenesis of the left jugular vein and sigmoid sinus, with dilated emissary veins beneath the masses [148]. Two Turkish siblings had a partially empty sella turcica [149].

Cardiovascular involvement is the main cause of death in the reports. Smith lists cardiomyopathy (including dilated), pulmonary hypertension and intracranial venous malformations [14]. Dilated cardiomyopathy, pulmonary hypertension (with ankyloglossia and prognathism) and a craniofacial vascular malformation have been the subject of isolated reports [150–152]. One man had dilated cardiomyopathy at 31 years, myocardial infarction at 34, at 37 years cerebral ischaemia with occlusion of the right internal carotid artery, stenosis of the left and thrombosis of the sigmoid sinuses and jugular veins, and died at 38 years of respiratory failure [153]. In the founding article, the Czech patient died of myocardial infarction at 19 years and an Egyptian patient of renal failure at 12 years [78].

Other occasional findings are mild skin laxity, umbilical hernia, hyperconvex nails, brachydactyly, phalangeal hypoplasia, sickle-shaped ribs, late menarche, hypogonadism, breast hypoplasia, early menopause, oligozoospermia, hypospadias, hepatomegaly, polycystic kidneys, nephrocalcinosis and hypothyroidism [14]. A four-year-old Algerian girl had right renal pelvic lithiasis and expansion of the scalp veins due to anomalies of the cerebral venous circulation [154]. In three Brazilian siblings, children of first cousins and older than the patients described until then, there were severe bone changes of the lower limbs [155]. Premature ovarian insufficiency has been demonstrated histologically [100]. Telogen effluvium and androgenetic-pattern alopecia with normal testosterone have been described [156]. The heterozygous parents of two Indian siblings had mild facial features and glaucomatous changes, an observation from a single family [157]. In a 30-year-old woman, pyoderma vegetans of the scalp was described, an association not previously reported [158].

3.2. The MBTPS2 spectrum

3.2.1. IFAP1 in boys

All affected boys have the triad of ichthyosis follicularis, scalp atrichia and photophobia [20]. Ichthyosis follicularis consists of non-inflammatory, generalised and symmetrical spiny follicular projections, most marked on the extensor surfaces and the scalp; the alopecia is congenital and non-scarring, affecting the scalp, eyebrows, eyelashes and body, and the newborn may have a collodion membrane [20]. Mégarbané's review, of about 40 patients, gives the frequencies in the table [20].

Photophobia may appear in the first year or later; corneal ulceration and superficial vascularisation lead to progressive scarring, and in boys the vascularisation progresses inexorably with loss of vision; the slit lamp shows diffuse punctate epithelial keratopathy and vascularising keratitis, with the anterior chamber, lens and fundus usually normal; cataract, nystagmus, astigmatism and myopia have been described [20]. A boy diagnosed at six days had hyperkeratotic eyelids, madarosis and lagophthalmos; at six months bilateral central epithelial defects appeared, and the optical coherence tomography findings were those of limbal stem cell dysfunction [159]. Meibomian gland dysfunction is part of the picture [160]. The palms and soles are usually spared, but palmoplantar keratoderma and overlap with Olmsted syndrome have been described [20, 115]. The dentition is normal [20].

Neurological involvement includes intellectual disability and seizures, olivocerebellar atrophy, malformation of the temporal lobes and hypoplasia of the corpus callosum; a patient with myoclonic-astatic seizures from the first year died at 33 years [17, 20]. Other findings are choanal atresia, large ears, omphalocele, Hirschsprung disease, small bowel stenosis, renal, cardiac and vertebral anomalies, cleft hand, cryptorchidism and recurrent infections [20].

3.2.2. BRESHECK

BRESHECK adds to the triad brain anomalies, intellectual disability, skeletal deformities (mainly vertebral), Hirschsprung disease, ear and eye anomalies, cleft palate or cryptorchidism and renal dysplasia or hypoplasia [17, 18]. The variant p.(Arg429His) is associated with the most severe phenotypes: a five-month-old boy, described by a Portuguese group, had brain anomalies, global delay, Hirschsprung disease and renal hypoplasia, as well as severe hypogammaglobulinaemia and a congenital rectourethral fistula [161]; a seven-year-old boy had a collodion membrane, severe ichthyosis, neurodevelopmental impairment, Hirschsprung disease and limbal stem cell deficiency [162]. With p.(Val256Leu), pulmonary stenosis, renal dysplasia, hypospadias, thrombocytopenia, anaemia, myelofibrosis and chronic diarrhoea have been described [111]. In the first Brazilian case with a molecular diagnosis there was absence of the right hand and radial aplasia [21].

3.2.3. Heterozygous women

Women may be asymptomatic or have hyperkeratotic lesions following Blaschko's lines, asymmetric body hair, patchy alopecia, photophobia in the first year and retinal vascular tortuosity [20]. Severe female forms have been described: a ten-year-old girl had congenital alopecia and diffuse follicular hyperkeratosis, without photophobia, and developed flexion contractures of the knees and equinus requiring surgery [163].

3.2.4. KFSD

X-linked KFSD begins with hyperkeratotic follicular papules on the scalp, followed by progressive scarring alopecia of the scalp, eyebrows and eyelashes, with photophobia and corneal dystrophy in childhood [9, 28]. There may be thickening of the skin of the neck, ears, palms and soles, thickened eyelids with blepharitis and ectropion, facial erythema and palmoplantar keratoderma [9, 26]. In a series of eight patients from seven families, the mean age at onset of alopecia was 21.25 years and midline scarring alopecia usually began after puberty; hyperkeratosis of vellus hair follicles was present in all and photophobia not always [27]. A Dutch newborn with p.(Ser213Trp) presented with erythroderma with a collodion membrane and non-scarring alopecia, with febrile seizures and hypohidrosis at eleven months [108]. Intellectual disability, atopy and deafness have been described as rare findings [29]. The autosomal dominant form is distinguished by marked facial erythema, extensive folliculitis, onychodystrophy and multiple caries due to enamel hypoplasia; the X-linked form more often has palmoplantar keratoderma and early onset [31]. In Bellet's family, the father's hair loss began at 27 years and the son's at 17 [30].

3.2.5. X-linked Olmsted syndrome

The Iranian patient described in 2007 had alopecia universalis and, from six months, hyperkeratotic lesions that progressed to massive hyperkeratoses with painful fissures on the palms and soles and verrucous plaques around the orifices and in the flexures [32]. The keratoderma may cause digital constriction up to autoamputation, and the keratotic areas may develop squamous cell carcinoma [9]. In the MBTPS2 forms, total alopecia and severe nail dystrophy are more frequent than in the TRPV3 forms [34].

3.2.6. Osteogenesis imperfecta type XIX

In the Thai family (twelve affected men, six examined), the proband had prenatal fractures of ribs and long bones and, at two years, moderate short stature, blue sclerae, pectus carinatum, bowing of the lower limbs and a lumbar bone mineral density Z-score of −4.7; the adults had fractures since gestation, short stature, white sclerae, scoliosis, anterior tibial bowing and osteopenia [50]. In the German family, the 26-year-old proband and his 68-year-old maternal uncle had numerous fractures in childhood, less frequent after puberty, kyphoscoliosis with vertebral wedging and a final height equivalent to that of a five- to six-year-old boy [50]. GeneReviews classifies the phenotype as type III or IV OI, without hearing loss, with generally white sclerae, rhizomelia and "popcorn" epiphyseal calcification [2].

3.3. The SREBF1 spectrum

In IFAP2, ichthyosis follicularis, photophobia and atrichia appear soon after birth; cataract, meibomian gland dysfunction and hyperkeratotic plaques appear in early childhood [51]. The skin shows ichthyosis follicularis or follicular hyperkeratosis, hyperkeratotic plaques, angular cheilitis and nail dystrophy; hair is absent or sparse, of variable calibre, on the scalp, eyebrows, eyelashes, axillae and pubis; electron microscopy shows a detached cuticle and trichorrhexis nodosa [51]. Two children with the variant at codon 527 had no apparent photophobia, and one had severe psoriasiform plaques on the extensor surfaces of the legs [164].

HMD has as its constant triad non-scarring alopecia, well-demarcated bright red mucosa (gingiva, hard palate) and psoriasiform perineal involvement; the panepithelial defect affects the oral, nasal, conjunctival, vaginal, cervical, perineal, urethral and bladder mucosae [52]. In a 2020 series, psoriasiform perineal intertrigo was present in six of seven patients and none had lung disease [52]. Interstitial lung disease with cor pulmonale in adults has been described in a single family and is not a diagnostic criterion [52]. In a French series from 2005 (one family with five affected members and three sporadic cases), the index case, a 14-year-old boy, had recurrent keratitis, generalised keratosis pilaris, perineal intertrigo, hypotrichosis and oral mucosal involvement; ultrastructure showed reduced desmosomes, and the authors proposed that the triad of non-scarring alopecia, well-demarcated erythema of the oral mucosa and psoriasiform perineal eruption suggests the diagnosis once the other follicular keratosis syndromes (IFAP, KID, Siemens) have been excluded [165]. Gastrointestinal manifestations — gastro-oesophageal reflux and oesophageal strictures or webs — were present in three of four patients in a 2026 series diagnosed with IFAP-SREBF1 [53].

Eye disease is the most consequential manifestation. Photophobia begins in the first months and is accompanied by meibomian gland dysfunction, recurrent vascularising keratitis with new vessels advancing from 360° of the periphery towards the centre and stromal opacity at the advancing front, cataract, nystagmus and low vision [9, 57]. In a boy followed from the first to the seventh year there was bilateral glaucoma [166]. A sporadic case of HMD had a favourable visual course over long follow-up, which the authors attributed to timely intervention [167]. In the historical HMD cases, corneal scarring and subcapsular cataract were present at 3.5 years, and one patient became blind despite radiation and grafting [52]. Hair loss may be cyclical and worsen with febrile episodes, with subsequent regrowth [57, 168]. Expressivity varies within the same family: a father with the variant p.(Arg527His) had mild occipital and temporal alopecia and mild ocular symptoms, and his son had blepharokeratoconjunctivitis, corneal ulcer and aphthae [168].

3.4. Alopecia with intellectual disability

In APMR1 to APMR3, the alopecia is total and congenital, with absence of eyebrows, eyelashes and axillary and pubic hair; teeth, nails, sweating and hearing are normal in the Pakistani families, and intellectual disability ranges from mild (IQ 53–61 in APMR2) to severe (IQ 25–30 in APMR3, with behavioural changes) [61, 62]. In the Iranian APMR1 family, IQ ranged from 40 to 54 [60]. Orphanet adds seizures, sensorineural deafness, psychomotor delay and hypertonia in some families [7].

In APMR4 (Besnard's series, 11 patients from seven families), alopecia was complete at birth in all; eight also had ichthyosis and/or erythroderma; intellectual disability was mild to severe; three had microcephaly; eight had epilepsy, with onset between birth and ten weeks; speech was absent or very limited in nine; seven had hypotonia and delayed or absent walking; magnetic resonance imaging was normal in two of nine and showed non-specific changes in seven; and four of six boys had genital anomalies [63]. Thin corpus callosum, cortical atrophy, cryptorchidism, micropenis, cerebellar involvement with ataxic gait, autism spectrum disorder, cataract and brain anomalies detected on prenatal ultrasound were described later [120, 169]. An Egyptian family added short stature, umbilical hernia, joint hyperextensibility and a dental mineralisation defect [170]. In a Chinese girl, compound heterozygous for NM_002340.6:c.401T>G p.(Val134Gly) and c.369C>G p.(Tyr123*), seizures began at four months, with status epilepticus, and only ceased with titrated clonazepam after valproate; she also had severe intellectual disability, developmental delay and dental dysplasia [10, 171]. The LSS phenotypes form a continuum: hypotrichosis simplex, alopecia with cataract, mutilating palmoplantar keratoderma with pseudo-ainhum, and APMR4 [172–174].

In the family with an ITGB6 variant, alopecia began in adolescence and was associated with mild to moderate intellectual disability and dentogingival anomalies [64].

3.5. FOXN1 deficiency

3.5.1. Biallelic form

The picture is that of a T−B+NK+ combined immunodeficiency from birth, with recurrent infections, oral candidiasis, diarrhoea and failure to thrive, congenital alopecia of the scalp, eyebrows and eyelashes, and dystrophy of all nails with ridging and pitting; without immune reconstitution it is fatal in the first year [9, 66]. Infections include viruses, bacteria and opportunistic agents; disseminated BCG disease, Mycobacterium bovis infection, human herpesvirus 6 and cytomegalovirus (CMV) have been described [66, 175]. In the cohort of Giardino and colleagues (18 patients from 11 families in nine countries), alopecia was present at onset in all homozygous or compound heterozygous patients except two, nail dystrophy in ten of 13, erythroderma or Omenn syndrome in seven of 13 (53.8%), and three patients developed Epstein-Barr virus-associated B-cell lymphoma; one patient with hypomorphic variants had an atypical late-onset form [70]. The form without alopecia or nail dystrophy (TIDTA) was described in a child with undetectable TRECs, who died at 12 months of viral infections before thymus implantation [67].

3.5.2. Heterozygous form

In Bosticardo's series, 21 newborns with low TRECs and four children with more severe infections had reduced CD8+ and CD4+ counts; 72% had recurrent respiratory or gastrointestinal infections, mainly viral, in the first years; ten had a small or absent thymic shadow, ten nail dystrophy and seven atopic dermatitis or eczema; none had alopecia [72]. Lymphopenia improved after two years, but most remained lymphopenic [72]. In adults (22 assessed, 17 from the village of Acerno), only six (27.3%) had a history of recurrent infections, 15 (68.2%) nail dystrophy, five atopic dermatitis and two men hair loss; CD4+ counts were generally normal and CD8+ below controls [72]. Among 55 carriers from Acerno, 39 had dystrophic nails, mainly koilonychia (28), canaliform dystrophy, Beau's lines and leukonychia [72]. In a series of five newborns followed for a median of 6.5 years, CD3+ counts rose within two years and four of five became asymptomatic [176].

3.6. Autosomal Olmsted syndrome

In the review by Duchatelet and Hovnanian, which gathered 73 patients from 59 publications between 1927 and December 2014, 44 were male and 26 female (about 63% boys), 14 had a TRPV3 variant and two an MBTPS2 variant, and most cases were sporadic [43]. The disease begins at birth, in the neonatal period or in early childhood, when the child starts to walk and grasp, and progresses slowly [43]. The palmoplantar keratoderma is bilateral and transgredient: it begins focally at pressure points, becomes diffuse, massive and thick, with deep and painful fissures, and may cause flexion contractures, digital constriction bands and spontaneous amputation, although pseudoainhum is not constant [43]. The periorificial keratotic plaques affect the mouth, nose, eyes, genitalia, anus, ears and umbilicus, and are absent in rare cases; there are also keratotic lesions of the thighs, arms, elbows, knees and flexures, linear streaks, follicular keratosis, cheilitis and chronic blepharitis, and the keratoderma may improve during febrile illnesses [43]. Pain is recorded in about 50% of cases and pruritus in about 16%, both causing insomnia and limitation of walking and grasping [43].

A subgroup has erythromelalgia — attacks of burning pain, pruritus, erythema, vasodilatation and warmth of the extremities triggered by heat and relieved by cold water — with neuropathic-type dysaesthesia and allodynia, sometimes with non-mutilating keratoderma and without periorificial plaques; by 2026, eight patients had been described before the Brazilian case published that year [45, 128, 177]. Most patients have hair changes (diffuse, universal or patchy alopecia, hypotrichosis, fine, curly, woolly, dry or brittle hair), with pili torti and trichorrhexis nodosa on microscopy; there is madarosis or, conversely, trichomegaly of the eyelashes [43]. The nails are dystrophic, with onychogryphosis, leukonychia, onycholysis, paronychia or absence [43]. Leukokeratosis of the tongue and buccal mucosa, hyperhidrosis or anhidrosis, corneal dystrophy and opacity, meibomian gland dysfunction, short stature, recurrent bacterial and Candida infections in the keratotic areas, dental anomalies with early tooth loss, hearing loss, osteoporosis and osteolysis of the hands and feet, joint hyperlaxity and, rarely, intellectual disability have been described [43]. Patients have increased susceptibility to verrucous carcinoma, including epithelioma cuniculatum of the sole, and to malignant melanoma in keratotic areas; in a Chinese patient with the TRPV3 p.(Val306Met) variant (published designation, without c. notation in the abstract), squamous cell carcinoma developed on the right sole [43, 178].

The TRPV3 spectrum includes attenuated forms: in Wilson's six families, referred to the International Pachyonychia Congenita project with no variant in the keratin genes, there was painful focal plantar keratoderma with onset between 18 months and nine years, thin nails with koilonychia, fine or normal hair, hyperhidrosis in four and periorificial plaques only transient or absent; some patients needed a wheelchair or crutches [46]. In patients with PERP variants, the shared features were cheilitis, periorificial plaques, transgredient keratoderma progressing to thick, fissured yellow plaques, hyperkeratotic nails and woolly yellow hair; a 40-year-old man had severe caries in the permanent dentition with extraction of all teeth at 38 years and a normal echocardiogram at 39 [42]. The authors knew of no patients with yellow hair and a TRPV3 variant [42].

4. Clinical Recognition and Warning Signs

4.1. The consultation for the child with congenital alopecia

The Oxford Desk Reference proposes, for unusual hair, teeth, nails and skin, a three-generation family tree with targeted questions about hair, teeth, nails, skin, deaths in childhood and clefts; a description of neonatal hair (whether it has ever been cut, whether it breaks); the eruption dates of the deciduous and permanent dentitions, and the shape, number and spacing of the teeth; the nails at birth and their growth rate; dry skin or "eczema"; sweating and heat intolerance; in women, mosaic patterns of skin colour, hair and sweating; susceptibility to infections and failure to thrive; and developmental delay or seizures [76]. The examination includes counting the teeth (20 in the complete deciduous dentition and 32 in the permanent dentition), inspecting the gum ridges in the newborn (flattening may indicate absent teeth) and examining each nail [76]. Saudubray points out that many neonatal and infantile alopecias are treatable small-molecule defects and should be excluded early [179].

4.2. Clues pointing to each entity

4.3. Warning and emergency signs

Biallelic FOXN1 deficiency is an immunological emergency: SCID occurs in about 1 in 30 000 live births, symptoms usually appear before seven months (failure to thrive, diarrhoea, oral candidiasis, Pneumocystis jirovecii pneumonia), the thymic shadow and tonsils are absent, and most children die in the first two years without immune reconstitution [77]. Alopecia at birth, before any erythroderma, distinguishes FOXN1 deficiency from Omenn syndrome of another cause [66]. In an athymic child, live vaccines (including BCG) are contraindicated and blood products must be irradiated and CMV-negative [69].

In GAPO, the emergency signs are headache, vomiting or papilloedema due to intracranial hypertension associated with craniosynostosis, focal neurological symptoms due to arterial disease or cerebral venous thrombosis, chest pain and dyspnoea (cardiomyopathy, myocardial infarction), visual loss due to glaucoma and a difficult airway at anaesthesia [99, 136, 144, 153]. In disorders of the SREBP pathway, persistent corneal erosions, severe photophobia and eye pain require prompt ophthalmological assessment, because the vascularisation progresses and may lead to blindness [20, 159]. In Olmsted syndrome, digital constriction and ulcerated or vegetating lesions in keratotic areas require assessment (risk of spontaneous amputation and of squamous cell carcinoma) [9].

4.4. Newborn screening

Newborn screening for SCID quantifies TRECs in dried blood spots; low or undetectable values indicate clinically significant T-cell lymphopenia (fewer than 1500 T cells/µL), with thresholds defined by each programme [4]. The test detects both the biallelic and the heterozygous forms of FOXN1 deficiency, and is now the usual route of identification [9, 74]. In a newborn with KFSD-X and erythroderma, newborn screening served to exclude SCID [108]. For the other entities in this article there is no newborn screening.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No entity in this article has formal diagnostic criteria published by a scientific society. Diagnosis is clinical and confirmed by molecular testing: biallelic pathogenic variants in ANTXR1 in GAPO; a hemizygous variant (or heterozygous in a symptomatic woman) in MBTPS2; a heterozygous variant in SREBF1; biallelic variants in LSS, AHSG or ITGB6 in APMR; and, in FOXN1 deficiency, the combination of the immunological diagnosis of athymia with variants in FOXN1 [9, 20, 69]. For KFSD in a clinical series, Lan and colleagues consider the basis of diagnosis to be involvement of terminal hairs (scalp, eyebrows or eyelashes) with hyperkeratosis of vellus hair follicles [27].

5.2. Entity-directed assessment

In GAPO, the orthopantomogram is the most useful non-molecular investigation, because it distinguishes pseudoanodontia (formed and retained teeth) from true anodontia and acquired loss; it is complemented by ophthalmological assessment of the optic disc and intraocular pressure, growth measurement, skeletal radiographs, cranial imaging (craniosynostosis) and cardiovascular, pulmonary and neurological assessment [9, 16]. Skin histology with matrix accumulation is a research observation and not a diagnostic test, and there is no blood test [9, 78].

In the MBTPS2 spectrum, dermatological examination and biopsy show dilated follicles with keratin plugs above the surface, reduced or absent sebaceous glands, normal sweat glands and, on electron microscopy, desmosomes reduced in number and size [20]. Histopathology is non-specific [20]. Slit-lamp examination assesses corneal dystrophy, blepharitis, ectropion and the meibomian glands; in women, the pattern of Blaschko's lines, linear hypohidrosis with the starch–iodine test and the X-inactivation pattern are sought; in the skeletal presentation, densitometry and radiographs [9]. In KFSD, trichoscopy shows perifollicular scaling, tufted hairs and loss of follicular openings, and histology shows fused infundibula, protrusion of the outer root sheath and inflammation [27].

In the SREBF1 spectrum, ophthalmological examination includes the meibomian glands and intraocular pressure; limbal impression cytology showed atypical epithelial cells in one patient; hair shaft analysis shows trichorrhexis nodosa; scalp histology shows orthokeratosis, acanthosis and dilated, plugged infundibula [9, 51, 58]. The serum lipid profile is normal [51].

In Olmsted syndrome, diagnosis rests on the association of bilateral, transgredient and mutilating palmoplantar keratoderma with periorificial keratotic plaques [43]. Histopathology shows epidermal hyperplasia, orthokeratosis, focal parakeratosis, hypergranulosis, acanthosis and an inflammatory infiltrate of the superficial dermis, with increased Ki-67 in the basal and suprabasal layers; it is non-specific and does not distinguish between keratodermas [43]. Plasma zinc excludes acrodermatitis enteropathica, which improves with oral zinc, and plasma tyrosine excludes tyrosinaemia type II [43, 180]. In incomplete forms, molecular testing is the most reliable means of confirming the diagnosis; the panel should include TRPV3, PERP and MBTPS2 and the genes of the keratodermas with which it is confused (pachyonychia keratin genes, GJB2, LOR, SLURP1, CTSC, TAT, SLC39A4) [43, 46].

In APMR4, plasma sterols are generally normal and do not exclude the diagnosis; the (S)-2,3-epoxysqualene/lanosterol ratio in forehead sebum, measured in research, reflects the enzymatic block [9, 122]. Slit-lamp examination looks for cataract, and brain magnetic resonance imaging is recommended by the authors of a review of 29 families [120].

In FOXN1 deficiency, immunological confirmation requires immunophenotyping with a T−B+NK+ pattern and a profound reduction of naive T cells (CD45RA+); congenital athymia is defined by fewer than 50 naive T cells/mm3 or less than 5% of total T cells with a naive phenotype [9, 69]. Proliferation to mitogens (phytohaemagglutinin, PHA) is reduced or absent [66]. The immunological diagnosis of athymia determines eligibility for thymus tissue implantation, and attribution to FOXN1 requires molecular testing, because 22q11.2 deletion and CHARGE syndrome are far more frequent [9, 71]. Older heterozygotes have an isolated reduction, predominantly CD8+ [9].

5.3. Molecular tests and their limits

Genomic investigation in the presence of features suggesting a syndrome may use a panel, exome or genome, with a microarray when the picture is malformative [76]. For athymia, the T−B+NK+ SCID panel (including IL7R and CD3D), exome or genome and microarray make it possible to distinguish thymic defects from haematopoietic defects, a distinction that decides between stem cell transplantation and thymus implantation [69].

The limits of the tests are concrete in these disorders. In GAPO, deletion of exon 3 of ANTXR1 is only detected with copy-number variant (CNV) analysis [16]. In MBTPS2, the intronic variants c.671-9T>G, c.225-6T>A and c.970+5G>A alter splicing, and their classification required minigene or patient RNA assays; an analysis limited to coding regions may fail to report them [22, 115]. In LSS, a synonymous variant at the exon 9 boundary (c.1011G>A) created a new splicing site [172]. In TRPV3, the interpretation of novel missense variants benefits from electrophysiological assays, and some patients with Olmsted syndrome have no variant in TRPV3, PERP or MBTPS2, so a negative result does not exclude the clinical diagnosis [43, 129]. In FOXN1, most variants are classified as VUS, and classification benefits from published functional assays [123, 124]. Apparent homozygosity may result from uniparental disomy, which is clarified by testing the parents [98]. In SREBF1 disorders, the report nomenclature must state the transcript: the same variant appears as p.Arg527 (NM_004176.5) or p.Arg557 (NM_001005291.3) [10]. The report should contain the gene, the versioned transcript, the HGVS nomenclature, zygosity and the class according to ACMG/AMP criteria; family segregation was decisive in several reports, such as the de novo variant of the Brazilian IFAP case, classified as likely pathogenic (PM2/PP3/PS2) [21].

5.4. Algorithm

5.5. Prenatal and preimplantation diagnosis

IFAP is not detectable by ultrasound; once the variant is known in the carrier mother, prenatal diagnosis can be offered [20]. In APMR4, fetal brain anomalies detected by ultrasound led to the first prenatal diagnosis of the disease, and in an Egyptian family an affected fetus was diagnosed prenatally [169, 170]. In GAPO, some features have prenatal onset [15]. In the village of Acerno, genetic screening identified a fetus homozygous for FOXN1 p.(Arg255*) [66]. In Olmsted syndrome, prenatal diagnosis is possible when the familial variant is known and forms part of counselling [43]. The European ichthyosis guidelines include prenatal diagnosis and preimplantation genetic testing within their scope [181].

6. Differential Diagnosis

6.1. Comparative table

6.2. Main differential diagnoses

The first differential diagnosis of neonatal alopecia is metabolic, because several small-molecule deficiencies are treatable: acrodermatitis enteropathica, biotin-responsive multiple carboxylase deficiency, calciferol defects, essential fatty acid deficiency, Menkes disease, methylmalonic and propionic acidurias, ornithine aminotransferase deficiency and urea cycle defects (argininosuccinic aciduria, citrullinaemia) [179].

In a child with alopecia and T-cell immunodeficiency, FOXN1 deficiency is distinguished from Omenn syndrome of other causes by alopecia present at birth, before the erythroderma, and persisting after transplantation [66]. The distinction between a thymic and a haematopoietic defect has therapeutic consequences: athymia is treated with thymus implantation and SCID with stem cell transplantation [69, 71]. Cartilage–hair hypoplasia also combines fine, sparse hair with cellular immunodeficiency, but is distinguished by short-limbed short stature present at birth, metaphyseal dysplasia and immunodeficiency of variable severity, which may manifest from the first months or only in the third decade; bone marrow transplantation corrected the immunodeficiency in some patients, with no effect on the bone changes [182, 183]. The 22q11.2 deletion (with complete DiGeorge syndrome and absence of T cells in fewer than 2%) and CHARGE syndrome are the most frequent causes of athymia, and SCID also enters the differential diagnosis [77].

In GAPO, the orthopantomogram separates pseudoanodontia — teeth present and retained — from the hypodontia of the ectodermal dysplasias [9, 76]. Fibrosis and hyalinisation bring GAPO close to the ANTXR2 disorders [78]. The aged appearance and fibroblast senescence recall the progerias, but GAPO fibroblasts do not accumulate prelamin A [107]. In Hutchinson-Gilford progeria, the appearance is normal at birth, alopecia appears in infancy and eruption is delayed, with hypodontia mainly of the permanent dentition [189]. Hallermann-Streiff syndrome shares the hypotrichosis and dental anomalies, but has microphthalmia and cataract in most patients, a thin beaked nose and natal teeth or partial anodontia [190].

In the IFAP spectrum, Mégarbané considers four main differential diagnoses among the syndromes with generalised ichthyosis and alopecia: dermotrichic syndrome, HMD, KID syndrome and KFSD; dermotrichic syndrome is distinguished by the skeletal and intestinal anomalies and IFAP by the ocular and respiratory disorders [17, 20]. Ichthyosis follicularis has also been described with GJB2 variants, including a child with KID syndrome [186]. In KID syndrome, vascularising keratitis (83%) and sensorineural deafness, documented from birth up to seven years, separate it from IFAP, and follicular keratosis and congenital alopecia are accessory findings [185]. Clouston syndrome, another connexin disorder, combines progressive alopecia, nail dystrophy and palmoplantar keratoderma, without ichthyosis follicularis and with only occasional photophobia [184]. Between IFAP1 and HMD/IFAP2, the differences are the inheritance (X-linked versus dominant), the bright red mucosae and the perineal involvement of HMD [52, 83]. X-linked Olmsted syndrome is distinguished from tyrosinaemia type II by the absence of ocular lesions and by normal tyrosine [3]. In tyrosinaemia type II, plasma tyrosine is usually between 1100 and 3300 µmol/L, and below about 1000 µmol/L symptoms do not usually occur [187]. Patients with tyrosinaemia type II have ocular lesions in about 75% of cases (photophobia, lacrimation and bilateral herpetic-like corneal ulcers), skin lesions in 80% (painful, non-pruritic hyperkeratotic plaques of the palms and soles with an erythematous rim) and neurological complications in 60%, and the differential diagnosis with Olmsted syndrome is mentioned in the textbook of metabolic diseases [180]. Among the severe keratodermas, periorificial plaques are the feature that separates Olmsted syndrome from Vohwinkel, Clouston, Papillon-Lefèvre and Haim-Munk syndromes, mal de Meleda, pachyonychia congenita and tyrosinaemia type II; acrodermatitis enteropathica, also periorificial, is excluded by zinc [43]. In pachyonychia congenita, manifestations are present at birth or by six months in about 80% of patients, the nails are thickened by one year of age and plantar pain results from blisters beneath the keratoderma [188]. Autosomal dominant KFSD is distinguished from the X-linked form by male-to-male transmission and by the inflammatory and dental features [31]. A 2026 review of cholesterol metabolism in the genodermatoses mentions KFSD-like phenotypes with CST6 variants and an alteration of polyamine homeostasis with MBTPS2 variants; the topical combination of statin and cholesterol has shown benefit in CHILD syndrome, porokeratosis and some autosomal recessive congenital ichthyoses, with no published data in IFAP or KFSD [191]. OI XIX is distinguished from PLS3 osteoporosis by the generalised dysplasia with fractures from gestation [50].

7. Treatments and Risk Management Strategies

7.1. General principles

None of the disorders of the class has disease-modifying therapy, with the exception of biallelic FOXN1 deficiency, in which thymus tissue implantation reconstitutes T-cell immunity [9, 71]. In the others, treatment is symptomatic and multidisciplinary and there are no specific guidelines: GeneReviews has no dedicated text for any of them, and the recommendations that follow come from reviews, case series, drug labels and the European guidelines on congenital ichthyoses, whose 2024 update covers topical and systemic therapies (oral retinoids, biologics and Janus kinase inhibitors), genetic counselling and prenatal diagnosis (part 1) and ocular, otorhinolaryngological, cutaneous, nutritional, and hair and nail complications (part 2) [181, 192]. In the previous version of the guideline (2019), patients with syndromic ichthyoses, including IFAP, may be candidates for oral retinoids, with closer monitoring of adverse effects [23]; the supplement to the 2024 update indicates the revised sections — vaccination and comorbidities as new sections, a modified recommendation on topical retinoids before ectropion surgery, new data on biologics — and keeps others unchanged, such as vitamin D deficiency [192]. No therapy restores hair in the scarring forms [9].

7.2. GAPO syndrome

There is no targeted therapy and no published surveillance schedule; the review of 105 cases considers early recognition, multidisciplinary care and genetic counselling essential, and identifies extracellular matrix dysregulation as a research target [9, 13]. Regular ophthalmological follow-up is recommended even when the first assessment is normal [14]. Glaucoma, present in all patients in an Egyptian series, requires intraocular pressure measurement and ophthalmological treatment [16]. In strabismus surgery, Tenon's capsule is inelastic and highly vascularised, which should be anticipated in planning [99].

Oral rehabilitation can be achieved with conventional complete dentures without surgery: in two patients with a molecular diagnosis, the alveolar ridge "ballooned" by the presence of both dentitions provided retention, normal muscle tone helped, and retention improved during follow-up [133]. The rehabilitation of two siblings has been described as part of individualised multidisciplinary care [193]. Because the dentition may change (late eruption of isolated teeth), oro-dental examination and follow-up orthopantomograms are recommended by the authors of an Egyptian series [94]. Osteomyelitis of the mandible has been described [134].

Craniosynostosis with intracranial hypertension was treated with cranial vault expansion; surgery was complicated by the absence of distinct periosteal layers, thin dura adherent to bone, pericranial adhesions and extensive venous bleeding [99, 144]. Anaesthesia requires preparation for a difficult airway, because of the craniofacial anomalies and, in one adult, aplasia of the sinuses and mastoid air cells [136]. Cardiovascular, pulmonary, skeletal and neurological assessment is part of care, given the cardiomyopathy, premature atherosclerosis and cerebral venous thrombosis described [9, 153]. The authors of a Tunisian report suggest brain magnetic resonance imaging and MR angiography to detect anomalies of the intracranial venous circulation, and those of a Turkish report radiological assessment of the sella turcica and endocrine follow-up [148, 149].

7.3. The MBTPS2 spectrum

7.3.1. Skin

Follicular hyperkeratosis is treated with topical keratolytics, urea preparations and emollients; topical retinoids are not suitable because they are irritant [20]. Oral acitretin produced a moderate response in some patients, with improvement of the skin and of corneal erosions, with no effect on the alopecia or photophobia [20]. In a six-year-old girl with IFAP and palmoplantar keratoderma, acitretin 10 mg/day produced skin improvement after one month, and in the Brazilian case of IFAP with severe congenital ichthyosis acitretin significantly improved the lesions (dose not stated) [21, 194]. Acitretin has an approved indication in Portugal for severe disorders of keratinisation, including congenital ichthyoses, so its use in IFAP falls within that indication [24].

The dosing reference is the previous version of the European guideline on congenital ichthyoses, which matches the range in the IFAP review (0.3–1 mg/kg/day) and the paediatric dose in the Portuguese SmPC [20, 23, 24]. The SmPC, cited for comparison, is more restrictive on maxima: 35 mg/day in children and, in adult disorders of keratinisation, 50 mg/day, below the 75 mg/day that the 2019 guideline gives as the maximum authorised by the EMA and that the SmPC reserves for maintenance in other indications [23, 24]. The 2024 update kept oral retinoids among the systemic therapies and added biologics and Janus kinase inhibitors [181]. Teratogenicity matters in adolescent and adult carriers with cutaneous expression [9].

In KFSD, oral isotretinoin was used with a response described as excellent in one patient and with hair regrowth after three months in another, an 18-year-old adolescent; the reports do not define a regimen, and use is off-label [9, 29, 195]. The 2019 European guideline prefers acitretin for long-term treatment and reserves isotretinoin or alitretinoin for women planning a pregnancy, because of their shorter half-life; it also records a report of possible worsening of corneal neovascularisation with isotretinoin in KID syndrome, a point to weigh in disorders with corneal vascularisation [23]. Retinoids are considered mainly in the inflammatory phase [9]. The 800 nm diode laser (depilation of inflamed follicles) has been described with success in one patient [196]. The autosomal dominant KFSD of Bellet's family was refractory to multiple treatments [30].

7.3.2. Eye

Corneal vascularisation in boys with IFAP progresses without response to topical corticosteroids, and intensive lubrication of the ocular surface is the mainstay of treatment [20]. In the boy with limbal stem cell dysfunction, the bilateral erosions were treated with intensive lubrication, prophylactic antibiotic and bilateral permanent lateral tarsorrhaphies at seven months, with subsequent stability [159]. Follow-up covers photophobia, corneal dystrophy, blepharitis and ectropion, with tinted lenses and photoprotection [9]. The European guideline on congenital ichthyoses recommends regular ophthalmological examination, with age-appropriate visual assessment, slit lamp (or a portable alternative) and cycloplegic refraction, at a frequency ranging from monthly to once or twice a year, and prolonged ocular lubrication with preservative-free drops when there is lagophthalmos [197]; it includes IFAP among the ichthyoses with meibomian gland dysfunction and with corneal scarring and vascularisation, and the 2024 update modified, in this area, only the recommendation on topical retinoids before ectropion surgery [192, 197]. The same guideline recommends looking for aggravating factors of alopecia (iron deficiency, thyroid dysfunction, drugs) and offering a wig to patients with marked alopecia [197]. In the first Brazilian case of IFAP, artificial tears and punctal occlusion improved the photophobia only slightly; it improved significantly, together with the corneal erosions, after three months of acitretin and amniotic membrane transplantation in the left eye [198].

7.3.3. BRESHECK, seizures and extracutaneous manifestations

BRESHECK requires neurodevelopmental assessment, renal imaging and follow-up, surgery for Hirschsprung disease, orthopaedics, correction of cryptorchidism and cleft palate, and immunological assessment, given the hypogammaglobulinaemia described [9, 161]. Seizures are treated as usual [20]. The severe knee and ankle contractures of a girl with IFAP improved gait after posterior soft-tissue release and Achilles tendon lengthening [163].

7.3.4. X-linked Olmsted syndrome

Keratotic plaques should be monitored because of the risk of squamous cell carcinoma, and digital constriction because of the risk of spontaneous amputation [9]. Conventional treatments (emollients, keratolytics, oral retinoids) are often insufficient [34]. In a 37-year-old man with p.(Phe464Ser), with no response to keratolytics, oral antibiotics and acitretin, oral erlotinib (an epidermal growth factor receptor, EGFR, inhibitor) at a dose of 150 mg on alternate days produced, at three months, significant improvement of the hyperkeratosis of the trunk, upper body and scalp, the start of growth of new nails and relief of pain and pruritus, without adverse effects and without effect on the alopecia; it was the first use described in the MBTPS2 form, after responses in TRPV3 Olmsted syndrome [34]. Erlotinib has no dermatological indication; the usual oncological dose in adults over 50 kg is 150 mg/day (with no maximum dose defined for dermatological use), with frequent gastrointestinal and cutaneous effects at that dose, according to the description of trial NCT06545695, which tests doses of 50 to 75 mg/day in keratin keratinopathies and does not include MBTPS2 [199]. This is evidence from a single case.

7.3.5. Osteogenesis imperfecta type XIX

OI XIX is treated like other forms of OI in a metabolic bone disease service, with no specific regimen published; the therapeutic approach to OI includes bisphosphonates [2, 9].

7.4. The SREBF1 spectrum

Treatment focuses on the eye: meibomian gland dysfunction, dry eye and ocular surface inflammation [9, 58]. In two infant girls with vascularising keratitis, topical corticosteroids produced partial regression, and the keratitis fluctuated for five years, which justifies prolonged ophthalmological follow-up [57]. In a child treated for meibomian dysfunction, dry eye and ocular surface inflammation, the corneal opacity improved greatly over seven years [58]. The bilateral glaucoma described in a boy justifies measurement of intraocular pressure [166]. The divergence from IFAP1, in which topical corticosteroids do not control the vascularisation, comes from isolated reports and not from direct comparison [20, 57].

In a child with IFAP type 2 and neurotrophic keratitis with bilateral epithelial defects refractory since birth, cenegermin (recombinant human nerve growth factor) led to complete epithelialisation by day 34 and recovery of corneal sensitivity, maintained two months after the end of treatment [200]. In the European Union, Oxervate® (cenegermin 20 µg/mL, eye drops) is authorised for moderate or severe neurotrophic keratitis in adults, at a dose of one drop in the conjunctival sac of the affected eye six times a day, every two hours, for eight weeks, and safety and efficacy below 18 years have not been established; paediatric use is off-label, and corticosteroids or preserved eye drops should be avoided during treatment [201].

The skin and mucosae are followed in dermatology; one patient with HMD had some response to oral zinc with normal plasma zinc, an isolated observation [52]. Hair regrowth after topical treatment of the scalp has been described, with occipital relapse during febrile episodes [168]. Gastro-oesophageal reflux and oesophageal strictures or webs require their own gastroenterological assessment [53].

7.5. Alopecia with intellectual disability and the LSS spectrum

Treatment is supportive: developmental and educational support, antiseizure medication in APMR4, surgery for visually significant cataract and dermatological care of the keratoderma [9]. In the Chinese child with cataract and hypotrichosis due to LSS, the cataract was operated on at three years [92]. Targeted approaches are experimental: lanosterol reduced crystallin aggregates in vitro and cataract severity in rabbit lenses and in dogs, with no efficacy demonstrated in patients, and a genetic study in UK Biobank did not support a protective role; LSS messenger RNA in lipid nanoparticles injected into the anterior chamber improved cataract in two rat models (preclinical, 2025); and a topical simvastatin ointment was used in LSS keratoderma in an off-label report [9, 119].

7.6. FOXN1 deficiency

7.6.1. Supportive care until reconstitution

The athymic child should be isolated and started on antibacterial, antiviral and antifungal prophylaxis, immunoglobulin replacement (B-cell function is reduced despite normal numbers), avoidance of all live vaccines, irradiated CMV-negative blood products, and avoidance of breastfeeding to prevent CMV transmission [69]. Oligoclonal T cells and high proliferation to mitogens — autologous graft-versus-host disease (GVHD), manifested by erythroderma, lymphadenopathy and organ infiltration — require immunosuppression with corticosteroids or calcineurin inhibitors [69]. The burden of disease under supportive care is high: in a survey of caregivers of 18 patients, all reported isolation and emotional burden, 78% financial difficulties and 78% frequent and prolonged hospitalisations [202].

7.6.2. Haematopoietic stem cell transplantation

Stem cell transplantation does not correct the stromal defect [66]. In athymia in general, survival after stem cell transplantation was about 41%, compared with up to 90% in SCID, with GVHD in about half [69]. In the Giardino cohort, survival was two of four with stem cell transplantation (survivors with an HLA-identical sibling donor and with an HLA-identical unrelated donor) and four of five with thymus transplantation, and the four patients without definitive treatment died in the first year [70]. Transplantation from an HLA-identical sibling donor containing mature T cells is one of the options mentioned in the 2017 review, and a Turkish patient treated in this way had immune reconstitution inflammatory syndrome with BCG adenitis [203, 204].

7.6.3. Allogeneic thymus tissue implantation (RETHYMIC®)

Allogeneic processed thymus tissue (RETHYMIC®, allogeneic processed thymus tissue–agdc; Sumitomo Pharma America) was approved by the FDA on 8 October 2021 for immune reconstitution in paediatric patients with congenital athymia; it is not indicated for SCID [71, 87]. The proposed mechanism is migration of T-cell progenitors from the recipient's marrow into the implanted tissue, where they differentiate into the patient's own naive T cells [71]. Administration is surgical, by implantation of tissue slices into the quadriceps muscle, at a dose of 5000 to 22 000 mm2 of RETHYMIC surface area per m2 of recipient body surface area (maximum 22 000 mm2/m2; up to 42 slices), calculated in advance by the manufacturer [71, 205]. Immunosuppression depends on the phenotype and the PHA response, as shown in the table.

Source of the table: FDA label [71].

Protective immune reconstitution is unlikely before six to twelve months, so infection control measures are maintained until there is thymic function [71]. Immunoglobulin is continued until the patient is off immunosuppression (at least 10% of CD3 naive), at least nine months have passed and the PHA response is normal; two months after stopping, trough IgG is measured and, if low, it is resumed for one year [71]. Pneumocystis jirovecii prophylaxis is continued until these criteria are met and CD4+ >200/mm3 [71]. Vaccines are given only when immunosuppression and immunoglobulin have been stopped, CD4+ counts are >200/mm3 and higher than CD8+, and PHA is normal, with a maximum of two inactivated vaccines per month [71]. Before implantation, anti-HLA antibodies are tested for, and HLA matching is required after previous stem cell or organ transplantation [71].

In the studies, GVHD occurred in 11 of 105 patients (10%), with six deaths; autoimmune events occurred in 37 (35%): thrombocytopenia in 13, neutropenia in nine, proteinuria in seven, haemolytic anaemia in seven, alopecia in four, hypothyroidism in two, autoimmune hepatitis in two and arthritis in two; the most frequent adverse reactions were hypertension (19%), cytokine release syndrome (18%), hypomagnesaemia (16%), rash (15%), renal impairment (12%) and thrombocytopenia (12%) [71]. Previous CMV infection was associated with death in the four patients who had it, and baseline renal impairment is a risk factor (five of ten died in the first year) [71]. There is a risk of lymphoproliferative disease and of transmission of infections through donor tissue [71].

The two patients with FOXN1 deficiency of Markert and colleagues — a child of consanguineous Portuguese parents and another of French–North African parents — had functional T- and B-cell reconstitution, a diverse repertoire and normal vaccine responses after thymus transplantation, and one developed autoimmune thyroiditis 1.6 years later [66]. An adult homozygous for p.(Arg255*) followed 19 years after transplantation cleared disseminated BCG infection and reconstituted naive cells with a diverse repertoire, but had a progressive decline in T-cell counts [206]. Younger age at implantation was associated with better naive reconstitution in an analysis of 76 children alive at one year, and at Great Ormond Street Hospital (GOSH, London) children detected by newborn screening reached transplantation younger and with fewer infections [207, 208].

7.6.4. Heterozygous form

The heterozygous phenotype is not athymia and is not an indication for thymus implantation; T-cell counts and function are monitored and infections are treated [9]. Because rare patients develop severe infections, surveillance is maintained, and stem cell transplantation is not curative: of the three patients transplanted in Bosticardo's series, one died and two remained lymphopenic [72]. The decision on live vaccines in these infants is individual and depends on T-cell function; it has been the subject of dedicated reports [69, 209]. Functional classification of the variant (loss of function, dominant-negative, benign) informs laboratory surveillance, prophylaxis and the decision on thymus implantation [124].

7.7. Autosomal Olmsted syndrome

There is no guideline or consensus for Olmsted syndrome, and all recommendations derive from case reports and series [43, 44]. Topical treatments (emollients such as petrolatum, keratolytics such as urea and salicylic acid, wet dressings, retinoids, corticosteroids and calcineurin inhibitors) and systemic treatments (acitretin, etretinate, isotretinoin, corticosteroids, methotrexate) gave weak to moderate and temporary relief; repeated partial excision or total excision with skin grafting was followed by recurrence [43, 44]. Control of pain and pruritus is a central part of treatment: analgesics and topical lidocaine in mild forms and, in neuropathic pain and erythromelalgia, anti-inflammatory drugs, anticonvulsants (carbamazepine, gabapentin, pregabalin), tricyclic antidepressants (amitriptyline, nortriptyline) and, as a last resort, tramadol; prolonged immersion in cold water relieves pain [43]. In children, tramadol is contraindicated below 12 years by the FDA, whereas the French SmPC for the drops allows it from 3 years, at a dose of 1 mg/kg per dose, 3 to 4 times a day, not exceeding 2 mg/kg or 100 mg per dose [210–212]. Acitretin is used with the doses and monitoring given for the MBTPS2 spectrum, extrapolated from the congenital ichthyoses [23, 24].

Transactivation of EGFR by TRPV3 provided the rationale for the use of erlotinib, an EGFR tyrosine kinase inhibitor [44, 47]. Greco and colleagues treated, between May 2018 and May 2019, three patients from two families (two brothers aged 15 and 17 years and a 13-year-old girl) with severe keratoderma, intolerable pain with erythromelalgia, severe growth retardation, anorexia and insomnia; two were wheelchair-bound, and in less than three months the hyperkeratosis and pain disappeared, the patients were able to wear shoes and walk again, the anorexia and insomnia remitted and the response was maintained at 12 months, with doses lower than oncological doses, adjusted by plasma levels, and mild to moderate adverse effects [47]. Zhang and colleagues treated four children (mean age 7 years) in the United States and in Curitiba: two first received sirolimus (an mTOR inhibitor), with improvement of the erythema and periorificial plaques, and switching to erlotinib improved the palmoplantar keratoderma; the other two, on erlotinib alone, had rapid and almost complete resolution of the keratoderma, and all maintained improvement in pain and pruritus without serious adverse effects [48]. In preschool-age twins, erlotinib gave partial improvement and the addition of acitretin reduced the residual keratoderma and pain; in a 23-month-old Hispanic boy, acitretin alone gave little improvement and the addition of erlotinib substantial recovery [213, 214]. Reports of erlotinib treatment followed from Australia, the United Kingdom, Turkey and Brazil, together with a Chinese case series on efficacy and safety [45, 215–219]. Trial NCT07090889 is evaluating oral KM-023 in healthy volunteers and then in patients with Olmsted syndrome for 12 weeks, and the erlotinib trial NCT06545695 does not include the genes of the syndrome [199, 220].

The evidence consists of reports and series without a control group, with selection of refractory cases and possible publication bias; there is no comparison between erlotinib and sirolimus and no long-term safety data in children beyond isolated cases with 52 months [45, 47, 48]. The absence of effect of erlotinib on alopecia was recorded in the MBTPS2 form [34]. Selective TRPV3 antagonists (trpvicine, FTP-THQ, dyclonine) and plant-derived inhibitors (osthole, α-mangostin, forsythoside B, isochlorogenic acids) are preclinical [44].

7.8. Regulatory status

7.9. Efficacy studies and registries

The RETHYMIC programme is an aggregation of open-label studies, without a concurrent control group; the comparison with natural history uses a historical control of 49 patients, and only two patients in the efficacy analysis had FOXN1 deficiency, so the figures mainly reflect complete DiGeorge syndrome [71]. The FOXN1 cohorts are small and retrospective, with no randomised comparison between thymus and stem cell transplantation [70]. There are no registered trials for GAPO, IFAP, KFSD, HMD, APMR or LSS deficiency; the KM-023 trial includes patients with Olmsted syndrome without genetic restriction in the summary, and the erlotinib trial NCT06545695 includes only keratinopathies due to keratin genes [199, 220]. The absence of registration does not prove an absence of research.

7.10. Developments in the last 12 months

7.11. Pregnancy, perioperative care and transition

Acitretin is teratogenic, and the Pregnancy Prevention Programme requires contraception and pregnancy tests during treatment and for three years afterwards [24]. In female MBTPS2 carriers with cutaneous expression, this point conditions the choice of therapy [9]. Erlotinib is teratogenic in animals and requires effective contraception during treatment and for one month after the last dose [221]. In GAPO, anaesthesia and surgery require planning of the airway and haemostasis, because of the craniofacial anomalies and the venous bleeding and dural adhesions described in cranial surgery [136, 144]. In a 20-year-old woman weighing 20 kg operated on for craniosynostosis, with obstructive sleep apnoea, macroglossia, Mallampati IV, limited neck extension and difficult venous access, induction was by inhalation; after extubation there was respiratory distress with saturation of 62% and two reintubations, followed by tracheostomy for 12 days, which the authors attributed to airway obstruction due to residual anaesthetic effect [225]. Anaesthesia for glaucoma surgery has also been described [226]. For thymus implantation, cardiac surgery planned in the preceding four weeks or the following three months was an exclusion criterion in the studies, and prolonged immunosuppression, including high-dose corticosteroids, should be avoided whenever possible [71]. In disorders with early vascular fibrosis (GAPO), progressive eye disease (IFAP, IFAP2/HMD) or intellectual disability (APMR), transition to adult care should maintain ophthalmology, cardiology and neurodevelopmental support; the sources consulted do not describe specific transition protocols [9, 14].

8. Reproductive Options and Family Counselling

8.1. Autosomal recessive disorders: GAPO, APMR and biallelic FOXN1 deficiency

The parents of an affected child are, as a rule, heterozygous, and the recurrence risk in each pregnancy is 25%; families with GAPO and APMR are frequently consanguineous [9, 60]. Before assuming two carriers, segregation should be studied: in GAPO, a child homozygous due to uniparental disomy of chromosome 2 had only one carrier parent, a situation in which the recurrence risk is low [98]. ANTXR1 carriers are usually asymptomatic, but the parents of two Indian siblings had mild facial features and glaucomatous changes, which justifies offering them ophthalmological assessment [157]. Heterozygous FOXN1 carriers are not clinically equivalent to silent carriers: they may have T-cell lymphopenia and nail dystrophy (TLIND), and in Acerno 39 of 55 carriers had dystrophic nails [72]. Once the variant is known, prenatal diagnosis and preimplantation genetic testing are possible; in APMR4, fetal brain anomalies allowed the disease to be suspected on ultrasound [169, 181].

8.2. X-linked disorders: the MBTPS2 spectrum

A carrier woman transmits the variant in 50% of pregnancies; sons who inherit it are affected, often severely, and heterozygous daughters have expression that depends on X inactivation and is unpredictable [9]. An affected man transmits the variant to all his daughters and to none of his sons [9]. A pattern along Blaschko's lines in the mother is a practical clue to carrier status, and the mother should be tested before the variant is considered de novo [9]. De novo variants have been described, as in the Brazilian case with p.(Pro243Ser) and in the Dutch newborn with p.(Ser213Trp), in whom maternal testing was negative; in these cases the recurrence risk is low but not zero, because germline mosaicism is not excluded, and by 2011 no cases of mosaicism had been described [20, 21, 108]. Mégarbané allowed for the possibility of dominant inheritance in some families with an affected mother and daughter without linear distribution of the lesions; since the discovery of SREBF1, these families should be re-evaluated for this gene [20, 55]. IFAP is not detectable by ultrasound, and prenatal diagnosis is performed when the maternal variant is known [20]. Severity cannot be predicted from the variant, as shown by the families with p.(Asn508Ser) and c.970+5G>A [113, 114].

8.3. Autosomal dominant disorders: SREBF1, AD-KFSD and FOXN1 haploinsufficiency

In the SREBF1 spectrum, many variants arise de novo and mother-to-daughter transmission is documented; an affected parent transmits the variant in 50% of pregnancies, with variable expressivity within the family, such as the father with mild alopecia and the son with more severe ocular and mucosal disease [51, 168]. In autosomal dominant KFSD, male-to-male transmission confirms the pattern [31]. In TLIND, the transmission risk is 50%, with incomplete penetrance [72]. The truncating gain-of-function variant p.(Ser430*) is a distinct entity and should not be interpreted by the same loss-of-function rule [84].

In Olmsted syndrome due to TRPV3, most cases are sporadic due to a de novo variant, such as the p.(Gly568Val) of the Brazilian girl, whose parents were not carriers; vertical transmission is documented (father and son with p.(Gln580Pro); patients in three generations in the European family with p.(Gly568Asp)), with a 50% risk for each child of a patient and variable expressivity [43, 45, 46]. In recessive families, the parents are heterozygous and the recurrence risk is 25%; a father heterozygous for p.(Gly568Cys) had no signs, which requires the variant to be interpreted in the context of the allele in trans [46, 128]. In the PERP form, the risk is 50% for the offspring of a heterozygous patient, and carriers of N-terminal loss-of-function variants are unaffected, but their homozygous offspring may have erythrokeratodermia [42]. Prenatal diagnosis and psychological support are part of counselling [43].

8.4. Counselling of minors and populations with consanguinity

Carrier testing in minors has no immediate clinical utility in the recessive forms, except when the carrier may have manifestations of their own, as in FOXN1 haploinsufficiency detected by newborn screening [74]. In girls from families with MBTPS2, carrier status may have clinical expression (skin, eye, contractures), which may justify testing when there are signs [20, 163]. In the community of Acerno, screening of 843 inhabitants (30% of the population) identified 55 carriers (6.52%) of the FOXN1 founder variant [66].

9. Special Considerations: Population Diversity and Epidemiology

9.1. What is known about frequency

None of the disorders has a validated population prevalence estimate; the available figures are counts of published cases and Orphanet classes [5–8]. GAPO has about 60 cases/families in Orphanet and 105 cases published between 1947 and 2025 (fewer than two per year), with no founder population demonstrated by haplotype study [5, 9, 13]. IFAP had about 40 cases in 2011 and about 60 in 2023; KFSD has the class <1/1 000 000 in Europe, not validated; Olmsted syndrome has 73 cases of all causes; OI XIX and X-linked Olmsted syndrome have no prevalence record of their own [9, 20, 21, 26, 33]. The count of 73 cases of Olmsted syndrome corresponds to the literature review up to December 2014, in which the authors considered a prevalence below 1/1 000 000 likely; in 2023 there were about 100 cases, more than 40 with a TRPV3 variant [43, 44]. APMR counts 15 families in Orphanet and about 14 individuals in a 2021 estimate, which proposed 1/1 000 000 [7, 60]. Hypotrichosis simplex and PPKCA due to LSS have 38 and 8 cases, respectively [9]. Biallelic FOXN1 deficiency has about 9–10 cases described up to 2021, and the heterozygous form, with no estimate, is increasingly detected by TREC screening [8, 9, 69]. For comparison, SCID of all causes occurs in about 1 in 30 000 live births [77].

9.2. Geographical distribution and founder populations

GAPO has been described in several ethnic groups, predominantly in populations with high consanguinity (Egypt, with 13 patients published up to 2024, and Turkey), and also in India, Pakistan, Syria, the Czech Republic and Sri Lanka [78, 94, 136, 156, 157]. In Brazil, nine of the 30 patients published up to 2008 were Brazilian, including three siblings who were children of first cousins; in 2005, four of the at least 19 known families were Brazilian, which led the authors to suggest a founder effect, without molecular confirmation [139, 155]. The FOXN1 founder variant p.(Arg255*) originates from an ancestral couple born in the early 19th century in Acerno (southern Italy), in a pedigree of 483 people over seven generations; the same variant was found in the homozygous state in a child of consanguineous Portuguese parents and in Indian patients [66, 70]. The Giardino cohort included patients from Italy, Portugal, France, Lebanon, India, Turkey, Saudi Arabia, Slovakia and Belarus [70]. In the MBTPS2 spectrum, p.(Asn508Ser) arose in Dutch, British, American and Chinese families with no demonstrated common ancestor, and c.970+5G>A in families from Pakistan, China and Argentina through recurrent mutation [28, 113, 114]. The SREBF1 p.(Arg527Cys) was found in Chinese, German, Congolese, Italian, African American and Indian patients [51]. APMR1 to APMR3 were mapped in consanguineous Pakistani and Iranian families [60]. Olmsted syndrome due to TRPV3 has been described in Chinese, Indian, Iranian, Arab, European and Latin American patients, with no founder population demonstrated; the largest molecular series are Chinese [43, 46, 127, 214]. PERP variants were identified in French and American cohorts, in children of Spanish and Mexican parents, and later in China [42, 130].

9.3. Portugal and Brazil

In Portugal, a boy with IFAP/BRESHECK due to p.(Arg429His), with severe hypogammaglobulinaemia and a rectourethral fistula, has been published, together with a patient with FOXN1 deficiency, the child of consanguineous Portuguese parents, treated with thymus transplantation and alive at 14.5 years in the 2021 cohort [66, 70, 161]. In Brazil, the first molecular diagnosis of IFAP (Curitiba) was published in 2023, and before that there was a single Brazilian case diagnosed clinically, published in 2011 [21, 198]. GAPO has at least nine published Brazilian patients, including an autopsy and two siblings with glaucoma and keratoconus without optic atrophy [101, 135, 139, 155]. In 2022 the first patient in the Americas with biallelic FOXN1 deficiency was described in Curitiba: a girl, the daughter of first cousins, homozygous for NM_001369369.1:c.814C>A p.(Pro272Thr), with alopecia universalis and nail dystrophy from birth, an Omenn phenotype, local BCG reaction and a brother who died at three months; thymus transplantation was indicated but not available in the country, and the patient died before two years of age of CMV infection refractory to ganciclovir [10, 175]. For Olmsted syndrome, the following have been published in Brazil: a seven-year-old girl with focal keratoderma and de novo p.(Gly568Val) (Porto Alegre), one of the four children in the sirolimus and erlotinib series treated in Curitiba, a boy from Rio de Janeiro with erythromelalgia treated with erlotinib and acitretin, and a report of erlotinib treatment in Porto Alegre; the sources consulted do not describe Portuguese cases [45, 46, 48, 219]. The sources consulted do not provide population frequencies for these countries.

9.4. Networks and associations

The relevant European Reference Networks are ERN-Skin (genodermatoses and ichthyoses; its neonatal erythroderma protocol was used in a KFSD-X case), ERN RITA (immunodeficiencies), ERN ITHACA (malformation syndromes and intellectual disability), ERN-EYE and ERN BOND (OI XIX) [108, 227]. Patient associations include FIRST (Foundation for Ichthyosis & Related Skin Types), the Ichthyosis Support Group in the United Kingdom, NFED (National Foundation for Ectodermal Dysplasias), IPOPI and the Immune Deficiency Foundation and, in Portugal, APDIP (Associação Portuguesa de Doentes com Imunodeficiências Primárias) [227].

10. Illustrative Clinical Case

10.1. IFAP/BRESHECK with limb malformations due to a de novo MBTPS2 variant (Brazil)

Migliavacca and colleagues described in 2023 the first molecular diagnosis of IFAP in Brazil [21]. The patient, a boy, was the child of a healthy, non-consanguineous couple (mother aged 31 and father aged 33 years) and had a healthy brother; the pregnancy was complicated by polyhydramnios and intrauterine growth restriction, and delivery was vaginal at 35 weeks, with a weight of 1850 g, length of 38 cm and head circumference of 30 cm, all below the 10th centile [21]. At birth he had a collodion membrane and congenital ichthyosis with taut facial skin, eclabium, ectropion, microcephaly, cryptorchidism, flattened rudimentary ears and absence of scalp hair, eyebrows and eyelashes; in the upper limbs the right hand was absent, there was bilateral shortening of the ulna with radial aplasia, fixed elbows and, on the right, only the fifth finger, and the fourth toe of the left foot was absent [21]. Echocardiography showed a patent foramen ovale, and tests of the cholesterol biosynthesis pathway were normal [21].

The family was assessed at the Pontifícia Universidade Católica do Paraná, in Curitiba, when the patient was 30 days old [21]. The karyotype and comparative genomic hybridisation microarray were normal. Exome sequencing of the patient, parents and brother identified the hemizygous variant NM_015884.4:c.727C>T p.(Pro243Ser) in MBTPS2, absent in the relatives (de novo), in a transmembrane domain, absent from population databases, with a single ClinVar entry as a VUS and classified by the authors as likely pathogenic (criteria PM2, PP3 and PS2); Sanger sequencing confirmed the variant and the segregation [10, 21]. Two heterozygous missense variants in ITGB4 were also found, whose contribution to the cutaneous picture the authors did not exclude [21]. Systemic acitretin significantly improved the skin lesions [21]. Figure 1 of the article shows the patient at one month of age, the pedigree, visualisation of the variant in the alignment file and Sanger confirmation: https://pmc.ncbi.nlm.nih.gov/articles/PMC10108828/figure/f1/ [21].

The case combines the IFAP triad with BRESHECK features (microcephaly, cryptorchidism, ear anomalies and skeletal malformations) and with a limb reduction malformation, rare in the spectrum; the authors mention an earlier patient with ulnar aplasia and oligodactyly and the variant p.(Cys334Tyr) [21]. The de novo variant implies a low recurrence risk for the parents, without excluding germline mosaicism, and a risk of 100% for daughters and zero for sons if the patient has children [9]. The acitretin dose was not published; in the newborn and infant, the decision follows the SmPC (about 0.5 mg/kg/day, only when alternatives are inadequate, with monitoring of growth and bone development) and should not be read as routine on the basis of one case [24].

10.2. The founding GAPO case

The founding GAPO article illustrates the natural course without targeted treatment: a Czech boy, assessed at 18 years with a height of −4 standard deviations, pseudoanodontia, alopecia, bilateral optic atrophy and abnormal visual evoked potentials, homozygous for NM_032208.3:c.505C>T p.(Arg169*), died of myocardial infarction at 19 years [10, 78]. Figure 1 of the article brings together the pedigrees and facial appearance of the four probands: https://pmc.ncbi.nlm.nih.gov/articles/PMC3644626/figure/fig1/ [78].

10.3. Olmsted syndrome due to TRPV3 with erythromelalgia treated with erlotinib and acitretin (Brazil)

Azulay-Abulafia and colleagues, in Rio de Janeiro, described in 2026 a term-born boy, the child of non-consanguineous parents with no family history of skin disease, who at five months began to have painful and pruritic palmoplantar keratoderma, progressively bilateral, with periorificial keratotic plaques [45]. On examination he had thick, asymmetric, localised or diffuse palmoplantar keratoderma, plaques around the anus, ears and mouth, leukokeratosis of the tongue, fine sparse hair and a left congenital clubfoot [45]. The next-generation sequencing panel identified the heterozygous variant NM_145068.4:c.1703G>T p.(Gly568Val) in TRPV3, absent in the parents; the article writes "c.1703>T", and the full notation was confirmed in VariantValidator [10, 45].

Topical treatments (retinoic acid 0.1%, urea 20%, corticosteroids, emollients) were ineffective; acitretin, started at 18 months at a dose of 1 mg/kg/day, moderately improved the calluses with very limited effect on pain [45]. Burning pain with pruritus, redness and warmth of the extremities, triggered by heat and relieved by cold, led to the diagnosis of erythromelalgia; gabapentin and tramadol reduced the pain only partly [45]. At four years, weighing 13 kg, oral erlotinib was added (50 mg/day alternating with 25 mg/day); within four weeks there was improvement in pain, pruritus, sleep, mobility and irritability, less use of analgesics, disappearance of the erythromelalgia attacks and improvement of the keratoderma, perioral plaques and leukokeratosis, and after 52 months of combined treatment there were no adverse effects and the patient had gained weight [45]. Figures 1 to 4 of the article document the keratoderma on acitretin alone and the course at 16, 46 and 52 months: https://pmc.ncbi.nlm.nih.gov/articles/PMC13049925/ [45].

The case shows the variability of the same variant (severe disease in Asian patients, focal keratoderma in another Brazilian child) and the off-label use of erlotinib in a young child, with a dose chosen by the authors and no guideline to support it; it should not be read as a standardised regimen [45, 46, 221].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

In GAPO, life expectancy is reduced in some patients: in the older reports, most died in the third or fourth decade, but there are older patients alive, and autopsies show interstitial fibrosis and coronary, cerebral and multiorgan atherosclerosis [14]. Deaths at 12 years (renal failure), at 19 (myocardial infarction) and at 38 (respiratory failure after cerebrovascular and coronary disease) are documented [78, 153]. In the first reports, two patients died at 39 and 37 years [228]. Intellectual development is frequently borderline [14].

In IFAP, life expectancy ranges from neonatal death to normal survival; the oldest patient described by 2011 was 33 years old, and cardiopulmonary complications were the main cause of death [20]. Visual loss due to progressive corneal vascularisation is the main functional determinant in boys [20]. In KFSD, scarring alopecia is progressive and permanent [9, 28]. In OI XIX, fractures decrease after puberty and final height is very short [50]. In the SREBF1 spectrum, keratitis fluctuates for years, may improve with prolonged treatment and may lead to blindness in severe forms [52, 57, 58]. In APMR4, prognosis is determined by the intellectual disability and the neonatal-onset epilepsy [63]. In Olmsted syndrome, reduced life expectancy has not been described, but progressive keratoderma and spontaneous amputation of digits may prevent grasping and walking and confine the patient to a wheelchair, pain and pruritus cause insomnia, corneal dystrophy may lead to blindness, and there is a risk of tumours in keratotic areas [43, 178]. In the series treated with erlotinib, remission of keratoderma and pain was accompanied by recovery of growth and social life [47].

In biallelic FOXN1 deficiency, without immune reconstitution the disease is fatal in the first year; in the Giardino cohort, the four patients without definitive treatment died in the first year, and four of five with thymus transplantation and two of four with stem cell transplantation survived [9, 70]. In the RETHYMIC programme, survival was 77% at one year and 76% at two years, and 94% of those alive at one year were alive with a median follow-up of 10.7 years; without treatment, two-year survival of 49 athymic patients was 6% [71]. Death after implantation is concentrated before reconstitution, mainly due to viral infection [69]. In the long term, T-cell counts may decline progressively [206]. In the heterozygous form, lymphopenia improves after two years and most adults have infrequent infections, with persistently low CD8+ counts [72].

11.2. Surveillance table

12. Summary and Final Considerations

Congenital alopecia syndromes with systemic involvement share an initial sign — absence or early loss of scalp hair, eyebrows and eyelashes — and differ in the organ that defines the prognosis. In GAPO syndrome, biallelic loss of function of ANTXR1 causes accumulation of extracellular matrix and fibrosis, with pseudoanodontia, glaucoma, craniosynostosis and early vascular disease; the orthopantomogram guides the diagnosis and follow-up is ophthalmological, dental, neurosurgical and cardiovascular. In the X-linked MBTPS2 spectrum, partial loss of intramembrane proteolysis of SREBPs and of ATF6 and OASIS produces the IFAP triad, BRESHECK, KFSD, Olmsted syndrome and osteogenesis imperfecta XIX, with partial genotype–phenotype correlation and expression in women dependent on X inactivation; treatment is symptomatic, with oral retinoids and intensive care of the ocular surface. In the dominant SREBF1 spectrum, IFAP2 and hereditary mucoepithelial dysplasia share the same codon (p.Arg527 in the MANE transcript, p.Arg557 in the old numbering), which supports the proposal of a single entity; vascularising keratitis, meibomian dysfunction and glaucoma require prolonged ophthalmological follow-up. Olmsted syndrome, in which alopecia accompanies a mutilating palmoplantar keratoderma and periorificial plaques, has three genes (TRPV3 with gain of function, PERP with dominant truncation, and MBTPS2), molecular diagnosis by panel after acrodermatitis enteropathica and tyrosinaemia type II have been excluded, and a response to erlotinib documented only in case reports and series. Alopecia–intellectual disability syndrome brings together a provisional gene (AHSG), two loci without a gene and the LSS spectrum, in which APMR4 is accompanied by neonatal epilepsy. FOXN1 deficiency is the entity in which early diagnosis changes the outcome: newborn screening by TRECs identifies the biallelic and heterozygous forms, athymia requires isolation, prophylaxis and thymus tissue implantation, approved in the United States and with orphan designation in the European Union, and the heterozygous form requires surveillance without transplantation. In all of them, genetic testing should include analysis of CNVs and intronic variants and state the transcript, and counselling depends on the inheritance, the possibility of de novo variants and uniparental disomy and, in the X-linked forms and FOXN1 haploinsufficiency, on expression in carriers.

13. References

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