CHAPTER 69
Genetic Defects of Nails and Nail Growth

Adam Rubin¹ and Amy S. Paller²

¹Department of Dermatology, University of Pennsylvania, Philadelphia, PA, USA

²Departments of Dermatology and Pediatrics, Northwestern University, Chicago, IL, USA

Pachyonychia congenita

Definition and nomenclature

Nail changes are a component of a large number of genodermatoses, especially the ectodermal dysplasias. Included in this chapter are some of the more common hereditary nail disorders that are not described in detail elsewhere and have distinctive manifestations. A list of additional non-syndromic and syndromic genodermatoses with nail abnormalities and their features is given in Table 69.1.

Table 69.1 Key genetic syndromes with known mutations that have nail manifestations. (Modified from Harper J, Oranje A, Prose N, eds. Textbook of Pediatric Dermatology, 2nd edn. Blackwell Publishing, with permission.)

				Phenotypic characteristics
Name (alternative names)	MIM number/primary ref.	Inh	Gene mutation	Nails	Other
Syndromic genodermatoses with nail anomalies
Acro-dermato-ungual-lacrimal-tooth syndrome (adult syndrome) [1]	103285	AD	TP63	Finger and toenail dysplasia	Skin: intensive freckling Other: lacrimal duct atresia; ectrodactyly, syndactyly; hypoplastic breasts and nipples
Adams–Oliver syndrome [2–5]	614814 100300 614219 615297	AD	RBPJ EOGT DOCK6 ARHGAP31	Nail aplasia	Cutis aplasia, syndactyly, microcephaly, short palpebral fissures, short distal phalanges, absent toes, asymmetric shortening of the hands, asymmetric reductions of the feet, intellectual deficits
Anaemia, dyserythropoietic congenital, type i [6]	224120	AR	CDAN1 (codanin 1)	Nail hypoplasia	Growth retardation, acrodysostosis, scoliosis
Ankyloblepharon-ectodermal defects–cleft lip and palate (AEC) syndrome [7]	106260	AD	TP63	Severe dystrophy	Skin: dry and smooth; palmoplantar hyperkeratosis with obliteration of dermatoglyphic patterns; occas reticulate hyperpigmentation; supernumerary nipples, severe recurrent scalp pustulation and erosion
					Face: ankyloblepharon filiforme adnatum with partial fusion of eyelids at birth; broad nasal bridge; hypoplastic maxilla; auricular abnormalities; cleft lip
					Other: lacrimal duct atresia; photophobia
Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (apeced) syndrome; autoimmune polyendocrinopathy syndrome, type I [8]	240300	AD	AIRE	Thickened and dystrophic	Oral candidiasis; autoimmune endocrinopathies (hypergonadotropic hypogonadism, insulin-dependent diabetes autoimmune thyroid diseases and pituitary defects); autoimmune or immunomediated gastrointestinal diseases (chronic atrophic gastritis, pernicious anaemia and malabsorption); chronic active hepatitis; autoimmune skin diseases (vitiligo and alopecia); keratoconjunctivitis; immunological defects (cellular and humoral); asplenia and cholelithiasis
Brachydactyly, type b1 [9]	113000	AD	ROR2 (receptor tyrosine kinase-like orphan receptor 2)	Nail aplasia, anonychia	Short middle phalanges, rudimentary or absent terminal phalanges, syndactyly
Coffin–Siris syndrome [10]	135900	AR?AD?	SMARCB1, SMARCA4, SMARCA2, ARID1A ARID1B	Abs to hypoplastic fifth fingernails and toenails; other nails occas hypoplastic or abs	Skin: dermatoglyphic changes; simian crease Other: coarse face with thick lips, wide mouth and nose, anteverted nostrils and low nasal bridge; retardation of psychomotor and growth development; hypotonia; lax joints; clinodactyly of the fifth fingers; general abs of terminal phalanges of fifth fingers and toes; general aplasia or variable hypoplasia of middle and prox phalanges of other fingers and toes; bilateral or unilateral dislocation of the radial heads; small or abs patella; frequent respiratory infections; umbilical and inguinal hernias; cleft palate; feeding problems in infancy; six lumbar vertebrae; short sternum; microcephaly
Corneal intraepithelial dyskeratosis and ectodermal dysplasia [11]	615225	AD	NLR family, pyrin domain containing 1 (NLRP1)	Dystrophic nails with prominent thickening of nail beds	Keratopathy with neovascularization and corneal opacification, palmoplantar hyperkeratosis, dyshidrosis, corneal dyskeratosis, pruritic hyperkeratotic scars, palmoplantar hyperkeratosis, chronic rhinitis, raspy voice.
Cranio-ectodermal syndrome (Levin syndrome I; Sensenbrenner syndrome) [12]	218330	AR	IFT122	Broad and short	Skin: dimples over elbows and knees; bilateral hallucal creases; single flexion crease on each toe; bilateral single palmar creases
					Skeletal: rhizomelic shortness (greatest in upper limbs); disproportionate shortness of the fibulae; pronounced shortness of middle and dist phalanges of toes and fingers; cutaneous syndactyly; clinodactyly; increased space between first and second toes; hallux valgus; dolichocephaly; gen osteoporosis; highly arched palate; sagittal suture synostosis; short and narrow thorax; pectus excavatum
					Other: hyperopia; myopia; nystagmus; frontal bossing; epicanthal folds and antimongoloid slant; full cheeks; posteriorly angulated pinnae with hypoplastic antihelix; hypotelorism; broad nasal bridge; anteverted nares; everted lower lip; capillary naevus on the forehead; multiple oral frenula; cong heart defects
Deafness and onychodystrophy (door syndrome) [13]	220500	AR	TBC1D24	Hypoplastic and dyst finger and toenails; anonychia	Skin: dermatoglyphic abnormalities
					Other: sensorineural deafness; apparently low-set ears; seizures and mental retardation; triphalangy of both thumbs and halluces; hypoplasia or aplasia of terminal phalanges of fingers and toes; occas clinodactyly and camptodactyly
Dyskeratosis congenita (X-linked) (Zinsser–Cole–Engman syndrome) [14]	305000	XR	DKC1	Dystrophy with late-onset paronychia occas leading to anonychia; hypoplasia	Skin: hyper- and hypomelanosis, telangiectatic erythema; ulcers; dry desquamation; atrophy; hyperkeratotic plaques (palmoplantar and over joints); premalignant lesions; abs fingerprints
					Eyes: blepharitis; ectropion of the lower lids; obliteration of the punctalacrimalia; bullous conjunctivitis; continuous lacrimation
					Other: sharp facial features; occas mental and growth retardation; Fanconi-like pancytopenia; premalignant leukoplakia on lips, mouth, anus, urethra and conjunctiva; frail skeletal structure; genital anomalies; oesophageal dysfunction and/or diverticulum; atrophic lingual papillae; gingivitis
Dyskeratosis congenita (autosomal dominant) [15–17]	127550 613990 613989	AD	TERC TINF2 TERT	Dystrophic	Skin: hyper- and hypomelanosis, telangiectatic erythema; ulcers; dry desquamation; atrophy; hyperkeratotic plaques (palmoplantar and over joints); premalignant lesions; abs fingerprints
					Eyes: blepharitis; ectropion of the lower lids; obliteration of the puncta lacrimalia; bullous conjunctivitis; continuous lacrimation
					Other: sharp facial features; occas mental and growth retardation; Fanconi-like pancytopenia; premalignant leukoplakia on lips, mouth, anus, urethra and conjunctiva; frail skeletal structure; genital anomalies; oesophageal dysfunction and/or diverticulum; atrophic lingual papillae; gingivitis
Dyskeratosis congenita (autosomal recessive) [18–23]	224230 613276 613987 613988 615190 613989	AR	NOLA3 C16orf57 NOLA2 WRAP53 RTEL1 TERT	Dystrophic	Skin: hyper- and hypomelanosis, telangiectatic erythema; ulcers; dry desquamation
					Other: pancytopenia; thrombocytopenia; small platelets; T-cell abnormalities; dystrophic fingers and toes
Ectodermal dysplasia with ectrodactyly and macular dystrophy [24]	225280	AR	CDH3	Dysplastic	Ectrodactyly; syndactyly; cleft hand; macular dystrophy
Ellis–van Creveld syndrome (chondroectodermal dysplasia, mesoectodermal dysplasia) [25] See Weyer acrofacial dysostosis, below	225500	AR	EVC (Ellis van Creveld syndrome), EVC2 (Ellis van Creveld syndrome 2)	Dysplastic (brittle, furrowed and underdeveloped)	Skin: eczema, petechiae are described in different patterns Short limbs, polydactyly, abnormal teeth
					Other: occas strabismus, cataract, coloboma of the iris, microphthalmia; exophthalmia; short-limbed dwarfism; bilateral postaxial polydactyly (gen of the hands); brachymetacarpy; thick and short bones of limbs; fusion of the hamate and capitate; clubfoot; genua valga; syndactyly; occas mild mental retardation; cong heart disease; respiratory difficulties; gingivolabial fusion; cleft palate; epispadia; hypospadias; hypoplastic genitalia
					Face: broad nose; occas cleft lip, frontal bossing and hypertelorism
Epidermolysis bullosa group
Epidermolysis bullosa dystrophica, autosomal recessive [26]	226600	AR	COL7A1 (collagen, type VII, alpha 1)	Anonychia, nail dystrophy, nail atrophy	Severe scarring blisters, contractures of hands and feet, mitten deformities, abnormal teeth, milia, gastrointestinal strictures
Epidermolysis bullosa, junctional, non-herlitz type [27]	226650	AR	COL17A1 (collagen XVII, alpha-1 polypeptide), LAMA3 (alpha-3 laminin), LAMB3 (beta-3 laminin), LAMC2 (gamma-2 laminin gene), ITGB4 (integrin, beta 4)	Nail dystrophy, fragile nails	Non-scarring blisters, abnormal teeth, plantar hyperkeratosis
Epidermolysis bullosa, lethal acantholytic [28]	609638	NK	DSP (desmoplakin)	Nail loss	Skin: universal alopecia, skin fragility, large sheets of skin detached, histopathology similar to pemphigus vulgaris
Epidermolysis bullosa simplex with muscular dystrophy [29]	226670	AR	PLEC (plectin)	Nail dystrophy	Progressive muscular dystrophy, blisters, atrophic scarring, alopecia
Erythrokeratodermia variabilis et progressiva (EKVP) [30]	133200	AD	GJA1 (gap junction protein alpha 1), (connexin 43)	Prominent porcelain-white proximal nails without dystrophy	Skin: normal skin at birth. In childhood, develop hyperpigmentation and scaling at sites of friction. This progresses to near-confluent corrugated hyperkeratosis. There is also darkening of the periorificial areas, palmoplantar keratoderma and transient figurate erythema. Erythema was induced by stress and warm conditions
Laryngoonychocutaneous syndrome [30]	245660	AR	LAMA3 (laminin, alpha 3)	Dystrophic nails, loss of nails	Hoarseness, skin ulcers, abnormal teeth, conjunctival injection and erosions
Focal dermal hypoplasia syndrome (Goltz syndrome) [31]	305600	XL	PORCN	Thin, spooned, narrow, grooved hypopigmented or abs	Skin: abs of skin from various parts at birth; areas of underdevelopment or thinness; linear hypo- or hyperpigmentation; telangiectasia; herniation of subcutaneous fat; multiple papillomas of mucous membranes and periorificial skin; follicular hyperkeratotic papules; angiofibromatous nodules around lips and anus; palmoplantar hyperkeratosis; occas dermatoglyphic changes
					Other: occas hearing loss; colobomas; microphthalmia; irregularity of pupils; clouding of cornea or vitreous; blue sclerae; lip papillomas; malformed auricles; asymmetry and notching of the alae nasi; pointed chin; triangular face; hypertelorism; mental retardation; short stature; syndactyly; polydactyly; hypoplasia of the external genitalia; umbilical and/or inguinal hernia; vertebral anomalies (scoliosis, spina bifida etc.) highly arched palate; gum papillomas; small breasts
Growth retardation–alopecia–pseudoanodontia–optic atrophy (gapo) [32]	230740	AR	ANTXR1	Hyperconvexity on fingers and toes is referred to in two patients	Skin: dry; redundant; fragile with inadequate wound healing (small, depressed scars); depigmented areas; unusual wrinkles; leather-like and thick on nape and upper back; abnormal dermatoglyphics
					Face: ‘small’ and ‘characteristic’; asymmetrical; craniofacial dysostosis; micrognathia; protruding and thickened lips; protruding auricles; prom supraorbital ridges; depressed nasal bridge; minor auricular malformations
					Other: sensorineural hypoacusia; optic atrophy; glaucoma; keratoconus; nystagmus; photophobia; dwarfism; occas mental retardation; symmetrical prox shortening of humeri; hyperextensible fingers; second and third toes smaller than the fourth; wide gap between hallux and second toes; wide anterior fontanelle; prom scalp veins; hepatosplenomegaly; bilateral choanal atresia; hyperplasia of sublingual connective tissue; hypoplasia of mammary glands; pectus excavatum; umbilical hernia; delayed bone maturation through childhood and adolescence
Haim-Munk syndrome [33]	245010	AR	CTSC (cathepsin C)	Onychogryphosis	Congenital palmoplantar keratosis, pes planus, periodontitis, arachnodactyly, acroosteolysis
Hyperphosphatasia with mental retardation syndrome 2 [34]	614749	AR	Phosphatidylinositol glycan anchor biosynthesis, class O (PIGO)	Nail hypoplasia, absent nails	Born with anal stenosis/anal atresia with perineal fistula; wide-set eyes, long palpebral fissures, short nose with broad nasal bridge and tip, tented mouth, Persistently elevated serum alkaline phosphatase (ALP), mental retardation
Hypohidrotic ectodermal dysplasia–X-linked (ED1; Christ–Siemens–Touraine (CST) syndrome) [35]	305100	XR	ED1	Gen normal; sometimes dyst or abs at birth and/or fragile and brittle with incomplete development	Skin: thin, smooth and dry due to hypoplasia or abs of sebaceous glands; occas pigmentation and dermatoglyphic changes; abs or supernumerary nipples and areolae
					Face: highly characteristic in persons who are severely affected (gen males) with thick and prom lips, depressed nasal bridge (saddle nose), frontal bossing, hypoplasia of the maxilla, wrinkles beneath the eyes, or around the eyes, nose and mouth and minor alterations of the auricles; the periorbital region is often more darkly pigmented than the rest of the body
					Other: occas conductive loss; photophobia; decreased function of the lacrimal glands; aplasia or hypoplasia of the lacrimal ducts; atrophic rhinitis; otitis media; decreased sense of taste and/or smell; atrophied mucous glands of the upper respiratory tract; respiratory difficulties; chronic pharyngitis and laryngitis; aplasia or hypoplasia of the mammary glands
Hypohidrotic ectodermal dysplasia–autosomal dominant [36]	129490	AD	EDAR	Gen normal; sometimes hypoplastic	Skin: smooth, thin, dry and hypoplastic
					Other: photophobia; hypoplasia of lacrimal ducts; decreased function of the lacrimal glands; saddle nose; thick and protruding lips; frontal bossing and prom auricles; chronic rhinitis, frequent respiratory infections
Hypohidrotic ectodermal dysplasia (autosomal recessive) [37]	224900	AR	EDAR	Gen normal; sometimes hypoplastic	Skin: smooth, thin, dry and hypoplastic
					Other: photophobia; hypoplasia of lacrimal ducts; decreased function of the lacrimal glands; saddle nose; thick and protruding lips; frontal bossing and prom auricles; chronic rhinitis, frequent respiratory infections
HED with immune deficiency [38]	300291	XD	IKBKG	Gen normal; sometimes hypoplastic	Milder ectodermal dysplasia features than classic HED; failure to thrive, recurrent infections of digestive tract; recurrent respiratory infections; dysgammaglobulinaemia
HED with immune deficiency, osteopetrosis and lymphoedema [38]	300301	XD	IKBKG	Gen normal; sometimes hypoplastic	Milder ectodermal dysplasia features than classic HED; failure to thrive, recurrent infections of digestive tract; recurrent respiratory infections; dysgammaglobulinaemia; osteopetrosis. Generally more severe phenotype than 300291
IFAP syndrome with or without BRESHECK syndrome [39]	308205	XL	MBTPS2 (membrane-bound transcription factor peptidase, site 2)	Dystrophic nails, paronychia, thick nails	IFAP: ichthyosis follicularis, atrichia and photophobia BRESHECK: brain anomalies, retardation, ectodermal dysplasia, skeletal deformities, Hirschsprung disease, ear/eye anomalies, cleft palate/cryptorchidism, and kidney dysplasia/hypoplasia
Incontinentia pigmenti (familial male-lethal type IP, Bloch–Sulzberger syndrome) [40]	308300	XL	IKBKG (inhibitor of kappa light polypeptide gene enhancer in B cells, kinase gamma)	Dystrophic in all or most of the fingers and toes in about one tenth of cases	Skin: vesicular-bullous eruption in the neonatal period followed or accompanied by verrucous lesions and bizarre pigmentation; pigmented macules may be present, alopecia
					Other: occas cong hearing loss; ophthalmological alterations in about one fifth of the patients include blindness, strabismus, cataract, uveitis, retrolental fibroplasias, optic nerve atrophy, microphthalmia; occas clubfoot, cleft palate, microcephaly; about one-third of the cases present severe CNS anomalies: spastic tetraplegia, hemiplegia, diplegia; epilepsy; mental retardation; occas short stature
Keratitis, ichthyosis and deafness (KID) syndrome [41]	148210	AD	GJB2	Abs at birth; delayed development; leukonychia and thickening (most marked in the fingernails); destructive dystrophy	Skin: ichthyosiform erythroderma with sebaceous dysfunction; furrowing around mouth and chin; erythematous hyperkeratotic plaques on elbows, knees, and the dorsa of hands and feet; marked thickening (leather-like consistency) of palms and soles; increased susceptibility to squamous cell carcinoma
					Other: cong sensorineural deafness; vascularisation of the cornea with pannus formation resulting in loss of vision; keratitis; occas decreased tear production; photophobia; bilateral flexion contractures at knees and elbows with tight heel cords
Limb–mammary syndrome [42]	603543	AD	TP63 (tumour protein p63)	Nail dysplasia	Hypoplasia/aplasia of the mammary glands; cleft lip/palate +/– bifid uvula; lacrimal duct atresia
Margarita Island ED (allelic to cleft lip/palate–ectodermal dysplasia syndrome (CLEPD1)) [43]	225060	AR	PVRL1	Dysplastic	Cleft lip/palate; syndactyly of fingers
Nail–patella syndrome [44]	161200		LMX1B (LIM homeobox transcription factor 1, beta)	Triangular lunulae, ulnar nail dystrophy, poorly formed lunulae, anonychia, dystrophic nails	Other: absent or hypoplastic patellae, elbow abnormalities, iliac horns, nephropathy, glaucoma, Lester sign (flower shape of pigmentation around the central portion of iris)
Odonto-onychodermal dysplasia [45]	257980	AR	WNT10A (wingless-type MMTV integration site family, member 10A)	Dystrophic nails	Skin: thickening of the palms and soles; erythematous lesions of face; thickening of the palmar skin with painful chafing
					Other: mild mental deficiency, peg-shaped incisor teeth, misshapen teeth, oligodontia, hypotrichosis, dry and sparse hair, thinning of the eyebrows.
Pachyonychia congenita [46]	167200 167210	AD	KRT6A KRT6B KRT6C KRT16 KRT17	Severe wedge-shaped thickening	Skin: focal palmoplantar keratoderma; verrucous lesions on the knees, elbows, buttocks, ankles, and popliteal regions; follicular keratoses/keratosis pilaris, multiple pilosebaceous cysts (steatocystomas)
					Other: oral leukokeratosis; hoarseness
Pallister–Hall syndrome [47]	146510	AD	GLI3	Nail dysplasia, hypoplastic nails	Hypothalamic hamartoblastoma, polydactyly, pituitary dysfunction, internal organ abnormalities
Palmoplantar keratoderma, mutilating, with periorificial keratotic plaques (Olmsted syndrome) [48, 49]	614594	AD	Transient receptor potential cation channel, subfamily V, member 3 (TRPV3)	Various degrees of nail dystrophy	Painful and disabiling palmoplantar keratoderma, spontaneous autoamputations, or ainhum-constrictions of the fingers, erythematous keratotic scaly periorificial lesions
Papillon–Lefèvre syndrome [50]	245000	AR	CTSC	Occas dyst (spoon-shaped and striated; onychogryphosis)	Skin: hyperkeratosis of the palmar and plantar surfaces with a tendency towards fissuring and cracking; dry and dirty-appearing on the dorsal surface of the arms and the ventral surface of the legs; occas eczema and erythema of the face as well as of the sacral and gluteal regions
					Other: severe gingivostomatitis; occas intracranial calcifications; abnormal liver function; renal abnormalities; gen osteoporosis
Poikiloderma with neutropenia (Navajo poikiloderma) [51]	604173	AR	USB1 (U6 snRNA biogenesis 1), C16orf57	Pachyonychia	Skin: eczematous rash at birth, becomes poikilodermatous over first 2 years of life
					Other: non-cyclical neutropenia, recurrent upper respiratory tract infections and chest infections, neutrophil dysfunction
					Similarity to Rothmund–Thompson syndrome (see below) but no mutations in RECQL4
Popliteal pterygium syndrome [52]	119500	AD	IRF6	Pyramidal skinfold extending from the base to the tip of the nails	Cleft palate/lip, popliteal webbing
Popliteal pterygium syndrome, lethal type [53]	263650	AR	RIPK4 (receptor-interacting serine-threonine kinase 4)	Anonychia, nail hypoplasia	Popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate syndactyly
Rapp–Hodgkin syndrome [54]	129400	AD?	TP63	Small narrow and dysplastic	Skin: dry and coarse; thickened over the extensor surface of the elbows and knees; hypoplastic dermatoglyphics
					Face: cleft lip; hypoplastic maxilla; mild frontal prominence; microstomia; mildly depressed nasal bridge; prom and malformed auricles
					Other: conductive loss (secondary to otitis media); chronic epiphora; corneal opacities; photophobia; atresia of puncta; ectropion; lacrimal papillae; short stature; occas syndactyly
					Absence of ankyloblepharon and severe erosive scalp dermatitis may distinguish Rapp–Hodgkin syndrome from AEC syndrome (see above)
Robinow syndrome, autosomal recessive [55]	268310	AR	ROR2 (receptor tyrosine kinase-like orphan receptor 2)	Anonychia	Short stature, rib and vertebral abnormalities, hypoplastic genitalia, empty sella, gum hypertrophy, face with hypertelorism, wide palpebral fissures, broad based nose
Rothmund–Thomson syndrome [56]	268400	AR	RECQL4	Frequently dyst	Skin: poikiloderma including atrophy, irregular pigmentation and telangiectasias beginning during the first 3–6 months; palmoplantar hyperkeratosis; sensitivity to sunlight; initial rash is red, elevated with oedematous patches appearing symmetrically on the cheeks, hands, forearms and buttocks and subsequently on the trunk and lower limbs; after a few years dry, scaling and atrophic skin develops with areas of hyperpigmentation, hypopigmentation and telangiectasia
					Other: cataract, usually bilateral (onset 3–6 years); occas degenerative lesions of the cornea; small hands and feet; short terminal phalanges, syndactyly: abs of metacarpals, rudimentary ulna and radius; increased risk of osteosarcoma; short stature; occas mental retardation; hypogonadism; cryptorchidism; skull abnormalities; scoliosis
Scalp–ear–nipple syndrome [57] (Finlay–Marks syndrome)	181270	AD	KCTD1	Brittle fingernails	Skin: raised firm scalp nodules
					Other: small tragi; cupped and protruding ears; absent/rudimentary nipples; breast aplasia; partial third/fourth finger syndactyly
Schinzel–Giedion midface-retraction syndrome [58]	269150	AR?	SETBP1	Narrow, deeply set, triangular and hyperconvex	Skin: abundant on the neck; hypoplastic nipples; hypoplastic dermal ridges; simian creases
					Face: saddle nose with depressed root and short bridge; high/protruding forehead; orbital hypertelorism; small/malformed auricles; anteverted nostrils; midface hypoplasia; facial haemangiomata
					Limbs: mesomelic brachymelia; hypoplasia of dist phalanges in hands and feet; short metacarpals of thumbs; talipes
					Other: severe mental retardation; growth retardation; abnormal EEG and seizures; spasticity; recurrent apnoeic spells; multiple wormian bones; wide cranial sutures and fontanelles; broad ribs, broad cortex and increased density of long tubular bones and vertebrae, hypoplastic/aplastic pubic bones; choanal stenosis; short and broad neck; short penis with hypospadias
Schopf–Schulz–Passarge syndrome [59] (cystic eyelids–palmoplantar keratosis–hypodontia–hypotrichosis)	224750	AR	WNT10A (wingless-type MMTV integration site family, member 10A)	Brittle with longitudinal and oblique furrows; onycholysis, hypoplastic nails, nail fragility, dystrophic nails	Skin: palmoplantar keratosis; telangiectatic facial skin; papules; multiple tumours with follicular differentiation Bird-like facies
					Other: bilateral early senile cataract; arteriosclerotic fundi; myopia; cysts of eyelids developing late
Sclerosteosis 1 [60]	269500	AR	SOST (sclerostin)	Nail dysplasia	Skeletal overgrowth, square appearance of jaw, syndactyly
Sclerosteosis 2 [61]	614305	NK	LRP4 (low density lipoprotein receptor related protein 4)	Hypoplastic nails, nails separated into 2 parts	Other: finger syndactyly, facial asymmetry, thickening of the skull and long bones
Short stature, onychodysplasia, facial dysmorphism, and hypotrichosis [62]	614813	AR	POC1 centriolar protein A (POC1A)	Hypoplastic fingernails	Severely short long bones, alopecia, growth retardation, macrocephaly, long, triangular face with prominent nose and small ears, unusual high-pitched voice. Clinodactyly, brachydactyly, hypoplastic distal phalanges, short and thick long bones
T-cell immunodeficiency, congenital alopecia, and nail dystrophy [63]	601705	AR	FOXN1 (forkhead box N1)	Ridging and pitting of nails	Other: congenital alopecia, severe T-cell immunodeficiency
Trichodento-osseous syndrome [64]	190320	AD	DLX3	Flat, thickened, misshapen and striated; brittle	Face: occas frontal bossing
					Others: occas clinodactyly; some of the calvarial sutures show evidence of premature fusion leading to mild to moderate dolichocephaly
Trichorhinophalangeal syndrome types I and III [65, 66]	190350 190351	AD	TRPS1	Occas thin, short, with long longitudinal grooves; flattened, koilonychia-like and normal in colour, racket thumbnails	Other: pear-shaped nose; long and wide philtrum; large, prom ears; occas exotropia and photophobia; short stature; increased susceptibility to upper respiratory tract infections; narrow palate; scoliosis; lordosis or kyphosis; pectus carinatum
					Limbs: brachymesophalangy; brachymetacarpy; brachymetatarsy; peripheral dysostosis with type 12 cone-shaped epiphyses at some of the middle phalanges of the hands (the joints are thickened); ulnar and radial deviation of the fingers; occas clinodactyly; winged scapulae; coxa valga; Perthes-like abnormalities
					(Type III: severe brachydactyly, short metacarpals, severe short stature)
Trichorhinophalangeal syndrome type II (Langer–Giedion syndrome) [67]	150230	AD	Loss of TRPS1 and EXT1 genes	Occas thin, short, with long longitudinal grooves; flattened, koilonychia-like and normal in colour; racket thumbnails	As above plus multiple cartilaginous exostoses; mental retardation is common
Trichothiodystrophy, photosensitive [68]	601675	AR	ERCC2, ERCC3, or GTF2H5	Brittle nails, dysplastic nails	Brittle hair, ichthyotic skin, short stature, mental retardation, photosensitivity
Ulnar-mammary syndrome [69]	181450	AD	TBX3	Missing digits, partial duplication of the nail on the 5th digit	Limb defects, ectopic and hypoplastic teeth, mammary gland hypoplasia, genital abnormalities, delayed puberty in males
Weaver syndrome [70]	277590	AD	EZH2 (enhancer of zeste homolog 2 (Drosophila)	Flat, deep set nails, narrow nails	Broad forehead, face, ocular hypertelorism, prominent wide philtrum
Weyer acrofacial dysostosis [71] (? milder AD form of Ellis van Creveld, MIM 225500, see above)	193530	AD	EVC2	Hypoplastic/ dysplastic	Other: short stature; postaxial polydactyly; short limbs; acrofacial dysostosis; abnormal mandible; hypotelorism; prominent ear antihelices
Witkop syndrome [72] (tooth and nail syndrome)	189500	AD	MSX1	Koilonychia; longitudinal ridging; nail pits, toenails more affected than fingernails	Lip eversion, hypodontia
Yunis–Varon syndrome [73]	216340	AR	FIG4	Absent thumbs, hypoplasia or loss of phalanx of other digits	Cleidocranial dysplasia, micrognathia, pelvic dysplasia, bilateral hip dislocation, retracted and poorly delineated lips, severe neurological involvement. Enlarged vacuoles are present in neurons, muscle, and cartilage
Non-syndromic genodermatoses with nail anomalies
Candidiasis, familial, 7 (candidiasis, familial chronic mucocutaneous, autosomal dominant) [74]	614162	AD	STAT1 (signal transducer and activator of transcription 1)	Candida onychomycosis and paronychia	Other: Candida infections of skin and mucous membranes
Darier disease [75]	124200	AD	ATP2A2	Nails with longitudinal erythronychia, longitudinal leukonychia and V-shaped nicks distally	Skin: verrucous papules and plaques in a seborrhoeic distribution, palmoplantar punctuate keratoses, thickening of the palms and soles, acrokeratosis verruciformis of Hopf Other: neuropsychiatric disorders including mild mental retardation, psychosis, and affective disorder
Ectodermal dysplasia 9, hair/nail type [76]	614931	AR	HOXC13 (homeobox C 13)	Micronychia and severe nail dystrophy	Other: congenital atrichia
Ectodermal dysplasia, pure hair and nail type [77]	602032	AD	KRT85	Congenital onychodystrophy; micronychia; onycholysis; onychorrhexis	Skin: folliculitis decalvans of neck
Ectodermal dysplasia/skin fragility syndrome (McGrath syndrome) [78]	604536	NK	PKP1 (plakophilin 1)	Thick and dystrophic nails	Other: severe blistering, desquamation, short and sparse hair, fragile skin, cracking and hyperkeratosis of palms and soles
Epidermolysis bullosa simplex, autosomal recessive 2 [79]	615425	AR	DST (Dystonin)	Nail dystrophy	Skin: trauma-induced blistering mostly on the feet and ankles
Epidermolysis bullosa simplex, Dowling Meara type [80]	131760	AD	KRT5 KRT14	Nail dystrophy, nail shedding, pincer nail deformity	Skin: generalized blisters that develop in clusters, and have a herpetiform appearance, can be haemorrhagic; blisters are mostly acral and can be periungual; hyperkeratosis of palms and soles/palmoplantar keratoderma
Hailey–Hailey disease (benign chronic pemphigus) [81]	169600	AD	ATP2C1	Longitudinal leukonychia of fingernails	Recurrent blisters in intertrigenous areas
Hidrotic ectodermal dysplasia (Clouston syndrome/ED2) [82]	129500	AD	GJB6 (connexin-30)	Hypoplastic nails, paronychia	Other: hair brittleness, alopecia, slow hair growth, palmoplantar hyperkeratosis
Kindler syndrome [83]	173650	AR	KIND1	Nail dystrophy, long thick cuticles	Congenital blistering, poikiloderma, skin atrophy, photosensitivity
Monilethrix [84]	158000	AD	KRT81, KRT83, KRT86	Occas dystrophic	Skin: keratosis pilaris, especially over nape of neck Hypotrichosis
Disorders with changes limited to the nails
Anonychia congenita [85]	206800	AR	R-spondin 4 (RSPO4)	Congenital absence of the nails, involving fingernails and/or toenails	No other associated abnormalities
Leukonychia totalis and/or partialis [86]	151600	AD and AR	PLCD1	White discoloration of a portion or all of multiple nails	No other confirmed associations
Nail disorder, non-syndromic congenital, 10 [87]	614157	AR	FZD6 (Frizzled family receptor 6)	Thick nails, hyponychia, onycholysis, claw-shaped nails

Abs, absent or absence; AD, autosomal dominant; AR, autosomal recessive; Dyst, dystrophic; Gen, generally or generalized; Occas, occasional; Prox, proximal; XR, X-linked recessive.

Pachyonychia congenita (PC) is a group disorders caused by dominant mutations in one of five genes encoding nail keratins. The clinical features seen in virtually all affected patients are toenail thickening and plantar keratoderma often associated with plantar pain (Table 69.2). Interestingly, despite the origin of the name of the disorder (pachy = large, onyx = nail), about 2% of PC patients lack nail involvement. Approximately 5000–10000 affected individuals have been described globally. PC was originally classified into two subtypes based on clinical features, the Jadassohn–Lewandowsky type (PC type 1; MIM 167200) and the Jackson–Lawler type (PC type 2; MIM 167210). Based on ­genotype–phenotype analyses of more than 250 patients showing that correlations of clinical features with underlying genotype were not absolute, this old terminology has been abandoned.

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Synonyms and inclusions

• Congenital pachyonychia
• Pachyonychia congenita syndrome
• Pachyonychia ichthyosiformis

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Table 69.2 Clinical features of pachyonychia congenita

Clinical feature	Overall %	PC-K6a %	PC-K6b %	PC-K6c %	PC-K16 %	PC-K17 %
Toenail dystrophy	97	99	98	59	96	99
Fingernail dystrophy	79	99	51	0	62	87
Plantar keratoderma	91	89	96	94	99	80
Plantar pain	96	97	100	100	97	89
Palmar keratoderma	59	55	41	18	78	52
Hoarseness	28	45	20	0	35	23
Oral leukokeratoses	56	88	29	18	40	27
Natal teeth	14	2	0	0	0	76
Cysts	59	67	73	24	27	92
Follicular hyperkeratoses	45	60	47	0	14	68

Modified from http://www.pachyonychia.org/pc_data.php

Pathophysiology

The keratins affected in individuals with PC are expressed in the nail bed, palmoplantar epidermis and mucosae. The new classification is based on genotype with gene defects in one of five different genes encoding keratins (KRT6A, KRT6B, KRT6C, KRT16 and KRT17) underlying the disorder. The new designations are PC-K6a, PC-K6b, PC-K6c, PC-K16 and PC-K17 [1]. Because keratins provide structural integrity to epithelial structures, mutations in these genes lead to cell fragility and compensatory hyperkeratosis. The severity of nail changes may be mutation dependent. For example, individuals with PC-K16 and p.Leu132Pro mutations have dystrophy of all fingernails, whereas those with p.Asn125Ser or p.Arg127Cys mutations in the same gene generally have no fingernail changes [2].

Clinical features

Based on data from the Pachyonychia Congenita Project, information about the clinical features of PC has been elucidated and is constantly being updated (http://www.pachyonychia.org/pc_data.php last accessed July 2014). The earliest and most common clinical feature is toenail dystrophy, which occurs overall in 97% of patients and is present at birth in 56.7% of patients [1] (Figure 69.1a, b). The 5^th and hallucal toenails are most often affected, and almost 70% have involvement of all 10 toenails, which usually become dystrophic concurrently. Fingernail dystrophy is noted in 79% of affected individuals [3] and is present at birth in almost 70% of patients [1] (Figure 69.1c). Most patients develop dystrophy simultaneously in all 10 fingernails and all patients with fingernail dystrophy also have toenail dystrophy. By 5 years of age, approximately 75% of patients have toenail and fingernail changes. The nails typically have marked subungual hyperkeratosis with a pinched V-shape, but can sometimes show premature nail termination. PC-K6c is the mildest form and may manifest only as plantar keratoderma without nail changes [4, 5]. PC-K6a and PC-K17 tend to be the most severe forms [6]. PC-K6a is the most common subtype, and affects 41.3% of PC patients [3]. Periungual infections (e.g. bacterial, candidal) have been reported in 93% of PC-K6a patients.

Figure 69.1 Nail dystrophy and plantar keratoderma are the principal features of pachyonychia congenita. (a) Toenails are dystrophic in this patient with PC-K17 (mutation K17 N92S). (b) Severe nail dystrophy and obvious plantar keratoderma in PC-K16 (mutation K16 L132P). (c) Fingernail dystrophy in PC-K6a (mutation K6a N172del). (d) Mild plantar keratoderma in PC-K6a (mutation K6a N171K). (e) Severe plantar keratoderma in PC-K16 (mutation K16 N125D). (Parts a–e courtesy of patients in the International Pachyonychia Congenita Research Registry (IPCRR) sponsored by the PC Project.) (f) Multiple sebaceous cysts on the neck of a patient with PC

(part f courtesy of Dr E. Sprecher).

Although the nail dystrophy can cause embarrassment, the often exquisitely painful plantar keratoderma exerts the greatest limitation on patients in terms of function and occurs overall in 96% of affected individuals [3] (Figure 69.1d, e). The plantar keratoderma is present in 10.4% of affected patients by 1 year of age, usually is present by 5 years of age in PC-K6a, -K16 and -K17 (comprising most patients), and occurs after 5 years of age in most individuals with milder forms, PC-K6b and -K6c [1]. Thickening tends to be focal and is most prominent at pressure points on the heel and ball of the foot; diffuse plantar involvement has occasionally been described [7]. Transgrediens spread (to the dorsal surface of the foot) has been described, especially with PC complicated by ­infection, trauma from standing or shoes, or exposure to foot moisture [8]. Plantar keratoderma is often complicated by painful erosions, fissures and/or bullae, which may be subcorneal and only detectable by imaging [9]. Palmar keratoderma occurs overall in fewer than 50% of patients, and only half of these show evidence of palmar keratoderma by 5 years of age [1].

Hoarseness and oral leukokeratoses typically present in the first year of life, particularly in babies with PC-K6a, leading to misdiagnosis of a variety of airway issues and thrush, respectively. Overall, 56% have oral leukokeratoses, with PC-K6a and PC-K17 having more severe or earlier onset of the oral leukokeratosis. Natal teeth in PC are virtually always a sign of PC-K17. Other features are pilosebaceous cysts (Figure 69.1f), found in most patients with PC-K6a, -K6b and -K17, and follicular hyperkeratoses. Cysts and hyperkeratoses most often develop in school-aged children, but can occur in younger children [1]. Hyperhidrosis affects more than 50% of PC patients, but usually is an issue in affected adults.

The nail changes lead to considerable embarrassment, particularly in adolescents, resulting in various strategies to conceal the nails [1]. The keratoderma impedes function, including walking, playing, schoolwork, a variety of other tasks and social development, especially in school-age patients and adults.

Nail trauma in children from shoe friction can lead to changes that resemble PC, but typically affects the 5^th toenail without other nail involvement. The genetic disorder most often confused with PC is hidrotic ectodermal dysplasia (Clouston syndrome; MIM 604418; see Chapter 67), which results from mutations in GJB6, encoding connexin 30. Patients typically show toenail and fingernail alterations at birth and painful keratoderma that can be indistinguishable from PC. Hearing loss, if present, and thin sparse hair during childhood (not a feature of PC unless semidominantly inherited with two dominantly mutant keratin genes [10]) are distinguishing features of hidrotic ectodermal dysplasia. Mutations on both alleles of FZD6, which encodes frizzled 6, a Wnt-signalling pathway receptor in the nail matrix, similarly lead to hypertrophic nail dystrophy at birth [11, 12].

Investigations

Genotyping is currently performed at no cost on a research basis for patients registered with the International Pachyonychia Congenita Research Registry (IPCRR) (www.pachyonychia.org last accessed July 2014).

Management

Mechanical treatment of the nails, such as filing, grinding and cutting is most effective, particularly after soaking the nails [13]. While antibiotics and antifungal therapy are helpful in managing secondary paronychia, they do not improve the nail dystrophy. Mechanical intervention can also ameliorate the keratoderma, but topical agents such as topical retinoids, steroids, keratolytics and moisturizers have not been found too helpful. Given the often debilitating pain, pain control management is key. Injection of botulinum toxin led to approximately 3 months of relief in eight described cases with and other hyperhidrosis [14], but a study from the International Pachyonychia Congenita Consortium found botulinum injections relatively ineffective [13]. Oral retinoids can decrease plantar thickening in 50% of patients, but only decreased plantar pain in about one-third of cases, led to worsening or no improvement in nails in 87% of patients, and caused unacceptable side effects, especially at higher doses (e.g. more than 25 mg acitretin daily) [15]. Administration of systemic rapamycin, which suppresses activation of mTOR but also expression of keratin 6a, partially reversed the plantar thickening and pain in PC-K6a during a 12-week trial but had unacceptable side effects; oral rapamycin did not improve nails [16]. Statins have also been shown to decrease expression of KRT6A [17], suggesting that a trial of oral statins could suppress keratin 6a expression in PC-K6a and allow normal keratin 6b and 6c proteins to compensate. siRNA injections directed against a mutant KRT6A led to dramatic improvement in the plantar keratoderma at the localized site of injection in the proof-of-concept human trial [18], but could not be sustained; use of microneedles for delivery or a cream formulation that traverses the plantar epidermal barrier are under investigation [19].

Resources

Patient resources

Support group: International Pachyonychia Congenita Research Registry or IPCRR (www.pachyonychia.org last accessed July 2014).

Dyskeratosis congenita

Definition and nomenclature

Dyskeratosis congenita (DC) is a heterogeneous group of inherited disorders characterized by nail dysplasia, oral leukoplakia, reticulated hyperpigmentation and a tendency towards bone marrow failure and squamous cell carcinoma.

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Synonyms and inclusions

• Zinsser–Engman–Cole syndrome

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Table 69.3 Underlying gene mutations in dyskeratosis congenita

Inheritance	MIM number	Gene location	Gene	Protein name	Protein function	Percentage of casesa
XLR	305000	Xq28	DKC1	Dyskerin	Component of telomerase complex that converts uridine residues of ribosomal RNA to pseudouridine	17–36
AD	613990	14q12	TINF2	TRF1-interacting nuclear factor 2	Shelterin complex component that protects telomere ends during DNA replication	11–24
AD	127550	3q26.2	TERC	Telomerase RNA component	Acts as a template for adding telomere repeats	6–10
AD	613989	5p15.33	TERT	Telomerase	Catalytic component of telomerase, which synthesizes telomere repeats	1–7
AR	613276	16q21	C16orf57	Mpn1 RNA exonuclease	Processes small nuclear RNAs posttranscriptionally	2
AR	224230	15q14	NOLA3	NOP10: nuclear protein, Family A, member 3	Small nucleolar RNA-binding protein that is associated with NHP2 and dyskerin in telomerase complex; involved in uridine to pseudouridine conversion	<1
AR	613987	5q35.3	NOLA2	NHP2: nuclear protein, Family A, member 2	Small nucleolar RNA-binding protein that is associated with NOP10 and dyskerin in telomerase complex; involved in uridine to pseudouridine conversion	<1
AR	613988	17p13.1	WRAP53	WD repeat-containing protein encoding RNA Antisense to p53; also called TCAB1: telomerase Cajal body protein 1	Important for telomerase trafficking	<1
AR	615190	20q13.33	RTEL1	Telomere replication	DNA helicase that is crucial for telomere maintenance, DNA repair and prevention of excess meiotic crossovers; interacts with TRF1	<1
AR	613989	5p15.33	TERT	Telomerase	Catalytic component of telomerase, which synthesizes telomere repeats	<1

^*Not all cases have been associated with a particular genotype, so that the numbers do not add to 100%.

AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive.

Introduction and general description

The prevalence of DC is estimated to be 1 in 1000 000 individuals. Most patients are male, and X-linked recessive inheritance accounts for approximately half of the cases. Females with heterozygous DCK1mutations may show clinical findings if skewed X-inactivation leads to significant expression of the mutant allele [1]. Autosomal recessive and autosomal dominant inheritance patterns have also been reported (see Table 69.3). The median age of diagnosis is 15 years, as many patients first present as teens or young adults.

Pathophysiology

Dyskeratosis congenita is considered a ‘telomeropathy’, because most patients show severe shortening of telomeres. Mutations in one of 10 genes are found in approximately 60% of patients [2, 3], and the protein products of these genes affect telomerase maintenance (see Table 69.3). Telomeres provide a repetitive template (TTAGGG) for repair at the 3’ ends of chromosomes that prevents the loss of genetically encoded information after replication. When too short, telomeres signal the arrest of cell proliferation and lead to senescence and apoptosis, which particularly impacts rapidly dividing cells. Telomerase catalyses DNA synthesis to maintain telomere length; the telomerase catalytic unit contains telomerase reverse transcriptase (TERT) and its template, telomerase RNA component (TERC). Other components of the telomerase complex that are mutated in DC are DKC1, encoding dyskerin, a small nucleolar protein that binds to RNA and TERC, and the stabilizers NHP2 and NOP10 [4]. The most common cause of DC is mutations in DKC1, but features of DC have been described from mutations affecting other telomerase complex components. Mutations in TINF2, a component of the shelterin complex that is essential for telomere maintenance, cause at least 10% of cases of DC. More recently, mutations have been found in the TCAB1 gene [5], encoding a protein that is key for trafficking of telomerase to Cajal bodies, which is where modifications and assembly of nucleoprotein complexes occur; its deficiency misdirects telomerase RNA so it cannot elongate telomeres. Mutations have also been found in: (i) RTEL1, a helicase that interacts with shelterin [6, 7], in CTC1 (conserved telomere maintenance component 1) [8]; and (ii) the C16orf57 gene [9].

Clinical features

The phenotype of DC varies widely, including among DC patients with mutations in the same gene. The minimal clinical criteria for DC diagnosis include having at least two major features and two minor features [10] (Table 69.4). The thin dystrophic nails usually appear first, between the ages of 5 and 13 years (Figure 69.2a, b). Mildly affected nails show ridging and longitudinal grooving; severely affected nails are shortened and show pterygium formation. Cutaneous changes usually develop after the onset of nail changes, most commonly during late childhood to teenage years. A fine reticulated dusky brown hyperpigmentation, sometimes surrounding hypopigmented, atrophic, telangiectatic patches (‘poikilodermatous’), on the face, neck, shoulders, upper back and thighs is characteristic (Figure 69.2b, c). Other cutaneous changes may include the following.

• Telangiectasia of the trunk.
• Redness and atrophy of the face with irregular macular hyperpigmentation.
• Acrocyanosis.
• Palmoplantar hyperkeratosis.
• Hyperhidrosis and bullae of the palms and soles.
• Wrinkled atrophic skin over the elbows, knees and penis.
• A diffuse atrophic, transparent and shiny appearance on the dorsal aspects of the hands and feet.

Table 69.4 Clinical features of dyskeratosis congenita

Major features (>75% of patients)

Nail dystrophy

Leukoplakia

Abnormal skin pigmentation

Bone marrow failure

Minor features

10–75% of patients

Short stature

Sparse hair or premature greying

Hyperhidrosis

Epiphora

Developmental delay

Pulmonary disease

Oesophageal stricture

Tooth decay and loss

<10% of patients

Squamous cell carcinoma

Intrauterine growth retardation

Gastrointestinal disease

Liver disease, enteropathy

Ataxia

Genitourinary issues

Hypogonadism, undescended testes, phimosis, urethral stricture

Microcephaly

Bone abnormalities

Osteoporosis, scoliosis, aseptic necrosis

Deafness

Figure 69.2 Nail dystrophy, poikiloderma and oral leukoplakia are the major mucocutaneous findings of dyskeratosis congenita. (a) Pterygium formation. (b) Nail dystrophy with poikiloderma (telangiectasia, atrophy and dyspigmentation) of the underlying thigh. (c) Poikiloderma on the thighs of a young woman.

(Courtesy of Dr E. Sprecher.) (d) Leukoplakia on the tongue. (e) Squamous cell carcinoma on the hand; mucosa is a more typical location. (Courtesy of Dr E. Sprecher.)

The hair of the scalp, eyebrows and eyelashes is often sparse and lustreless.

Mucous membrane changes consist of leukoplakia (Figure 69.2d), and rarely blisters and erosions, of the oral and anal mucosae, oesophagus and urethra. Periodontitis may also develop. Similar changes of the tarsal conjunctivae may result in atresia of the lacrimal ducts, excessive lacrimation, chronic blepharitis, conjunctivitis and ectropion. The teeth tend to be defective and subject to early decay.

Overall, almost 90% of patients develop life-threatening bone marrow failure, characterized by severe aplastic anaemia with neutropenia, splenomegaly and a haemorrhagic diathesis. Acute myeloid leukaemia and myelodysplastic syndrome have also been described. Pulmonary fibrosis and hepatic cirrhosis are other life-threatening complications. Isolated idiopathic pulmonary fibrosis, liver disease, aplastic anaemia, myelodysplasia and leukaemia have each been described in patients found to have mutations in DC genes, especially single allele mutations in TERT and TERC. Epithelial tumours often first develop by the mid-teens, frequently in areas of mucosa with leukoplakia. Squamous cell carcinoma of the tongue is most common, but cutaneous squamous cell carcinoma can also occur (Figure 69.2e). Patients are at increased risk for the development of head and neck, as well as anogenital, squamous cell carcinomas. These carcinomas are not driven by human papillomavirus (HPV) infection and thus HPV vaccination is not predicted to decrease the risk. Rarely, common variable immunodeficiency is the initial presentation of DC [11].

A severe variant, Hoyeraal–Hreidarsson syndrome, shows the major features of DC, but in addition cerebellar hypoplasia, developmental delay, intrauterine growth retardation, and sometimes severe immunodeficiency, enteropathy and/or aplastic anaemia. Most patients have mutations in DKC1, but mutations in TERC, TERT, TINF2 or RTEL1 have been described [7]. Another severe variant of DC, Revesz syndrome, has bilateral exudative retinopathy, cerebellar hypoplasia and growth retardation, as well as nail dystrophy, fine hair and bone marrow hypoplasia [12].

The average life expectancy is 44 years. Patients usually die of bone marrow failure (∼60–70%), pulmonary disease (∼10–15%) or malignancy (∼10%).

The pterygium nail changes of DC can be seen in patients with lichen planus and graft-versus-host disease. The poikilodermatous change is sometimes confused with Rothmund-Thomson syndrome (RECQL4 mutations), epidermolysis bullosa simplex with mottled pigmentation (usually KRT5 mutation), Naegeli-Franceschetti-Jadassohn syndrome/dermatopathia pigmentosa reticularis (KRT14 mutation) or Clericuzio-type poikiloderma with neutropenia (another C16orf57 mutation) [13].

Investigations

Screening for DC is best performed by flow cytometry and fluorescence in situ hybridization (flow-FISH) of leukocyte subsets [10] to detect telomere shortening. Recommended disease surveillance includes biannual blood counts, bone marrow evaluations annually, hepatic ultrasounds, annual pulmonary functional tests and skin cancer screening.

Management

Treatment of bone marrow failure is recommended with a haemoglobin persistently below 8 g/dL, platelets <30 000/mm³ and neutrophils <1000/mm³. Allogeneic stem cell transplantation is usually performed for bone marrow failure, but the 10-year survival probability is 30% with mortality generally attributed to pulmonary or vascular complications related to disease progression [14] or toxicity related to myeloablative regimens. If a matched donor without genetic and clinical evidence of DC is available, stem cell transplant should be considered, but carries substantial risk, including an increased risk of pulmonary fibrosis with graft-versus-host disease. Long-term survival after transplantation has been poor. A trial of androgens, such as oxymetholone or danazol, may be considered before transplantation from an unrelated donor, and improves blood counts in 60% of treated patients [15]; however, androgens may cause hepatic tumours, and the combination of androgen and granulocyte colony-stimulating factor (G-CSF) has led to splenic rupture. Management of patients otherwise consists of bougienage for oesophageal stenosis; fulguration, curettage and surgical excision of leukokeratosis of the buccal and anal mucosae; and lifelong regular supervision for early detection of mucosal or cutaneous carcinomas.

Resources

Patient resources

Support group: Dyskeratosis Congenita Outreach (http://www.dcoutreach.org/ last accessed July 2014).

Nail–patella syndrome

Definition and nomenclature

Nail–patella syndrome is an autosomal dominant disorder classically characterized by nail changes and dystrophy of the patella and iliac horns.

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Synonyms and inclusions

• Hereditary onycho-osteodysplasia (HOOD)
• Fong disease
• Turner–Kieser syndrome

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Introduction and general description

Nail–patella syndrome, a disorder of nail and bone dysplasia, has an estimated prevalence of 1 in 50 000 individuals, although the prevalence could be higher, given the many affected individuals with a mild phenotype [1] (Table 69.5). De novo mutations occur in 12% of affected individuals (i.e. 88% have an affected parent). Interfamilial and intrafamiliar variability is seen. The diagnosis is often missed for several generations, although ­features tend to be present at birth. Males and females are affected equally.

Table 69.5 Clinical features of nail–patella syndrome

Features	% Of patients
Nail changes, especially triangular lunula	98
Small or absent patella	74
Elbow deformity	70
Iliac horns	70
Renal dysfunction	40
End-stage renal disease	5
Ocular hypertension, glaucoma	33

Pathophysiology

Nail–patella syndrome (NPS) results from mutations in LMX1B at chromosome 9q33.3, which encodes the LIM homeobox transcription factor 1-β. LIMX1B is induced by Wnt7a and is required for establishing dorsoventral polarity in the dorsal limb mesenchyme during development, as well as in the development of the kidneys, eyes and bones. For additional details on the anatomy and embryological development of the nails, the reader is referred to Chapter 95. Mutations in LMX1B can also lead to nail–patella-like renal disease, in which skeletal and nail findings are absent [2].

Clinical features

The nails may be absent or underdeveloped and discoloured, split, ridged or pitted, but nail dysplasia with the characteristic triangular lunula instead of the crescent-shaped lunula occurs in most affected individuals and may be the only feature (Figure 69.3). Changes are usually bilateral, symmetrical and may be present at birth. The fingernails are more likely to be affected than the toenails, and the thumbnails are usually the most severely affected, with severity decreasing from the index toward the 5th fingers. The ulnar side of the fingernail is more severely affected than the radial side. Patients show flexion of the distal interphalangeal joints but hyperextension of the proximal interphalangeal joints, leading to ‘swan-necking’. Creases overlying the distal interphalangeal joints tend to be absent.

Figure 69.3 Nail dystrophy with triangular lunula of the nail–patella syndrome.

(Courtesy of Dr Mark Holzberg.)

Knees are involved in 74% of patients [3] and tend to have a flattened profile. Patellar involvement is often asymmetrical and commonly characterized by small irregularly shaped or absent patella with recurrent dislocation or subluxation. Flexion contractures and early degenerative arthritis are common; as a result, patients often develop knee pain, locking, instability and inability to straighten the knee. Elbow involvement also is often asymmetrical and occurs in 70% of individuals [3]. The characteristic iliac horns are bilateral conical bone projections that extend posteriorly and laterally from the centre of the pelvic iliac bones. They affect approximately 70% of affected individuals, are asymptomatic and are pathognomonic for the disorder. Renal changes occur in 30–50% of affected individuals, initially as proteinuria with or without haematuria and hypertension; only 5% of patients show end-stage renal disease, which may occur rapidly or develop gradually. Ocular hypertension and primary open-angle glaucoma occur overall in one-third of patients and more often and at a younger age. Crumbling teeth and thin dental enamel have been described [3]. Patients have an increased risk of attention deficit hyperactivity disorder and major depressive disorder, possibly because of mesencephalic dopaminergic neurology pathway abnormalities [4]. Sensorineural hearing loss has been described.

Investigations

The diagnosis of NPS is based on clinical findings, supplemented by laboratory testing to show the radiographic changes and evidence of renal disease, if present. Radiographic evaluation is necessary to detect the iliac horns, although large horns may be palpable. X-rays are also helpful to confirm the bony changes of the elbows and knees. Characteristic modifications of the glomerular basement membrane can be observed by electron microscopy.

Management

No treatment intervention is needed for the nail abnormalities. Orthopaedic complications are treated by physiotherapy, splinting or bracing, analgesics and occasionally surgery. However, chronic administration of non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided because of the risk of renal disease. Annual monitoring for hypertension, renal disease (urinalysis) and glaucoma is recommended. Hypertension should be controlled medically but renal transplantation is occasionally necessary. Dual-energy X-ray absorptiometry (DEXA) bone density scans are recommended beginning in young adults.

Resources

Patient resources

Support groups: Nail Patella Syndrome Worldwide (www.npsw.org) and Nail Patella Syndrome UK (www.npsuk.org) (both last accessed July 2014).

Hereditary anonychia

Definition and nomenclature

Hereditary anonychia is an autosomal recessive disorder characterized by isolated congenital anonychia or hypoplasia of the fingernails and/or toenails.

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Synonyms and inclusions

• Congenital anonychia
• Onychodystrophy-anonychia

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General description of hereditary anonychia

In hereditary anonychia, anonychia or hypoplasia of the fingernails and/or toenails is congenital and usually involves all of the nails. The disorder results from mutations in the R-spondin 4 (RSPO4) gene on chromosome 20p13 [1, 2]. RSPO4 is only expressed in the mesenchymal tissue underlying the digit tip epithelium [3]. RSPO4 is a member of the R-spondin family of secreted proteins, which activates Wnt/β-catenin signalling and presumably Wnt7a.

References

1. Avitan-Hersh E, Indelman M, Bergman R, Sprecher E. ADULT syndrome caused by a mutation previously associated with EEC syndrome. Pediatr Dermatol 2010 Nov–Dec;27(6):643–5.
2. Hassed SJ, Wiley GB, Wang S, et al. RBPJ mutations identified in two families affected by Adams-Oliver syndrome. Am J Hum Genet 2012 Aug 10;91(2):391–5.
3. Shaheen R, Aglan M, Keppler-Noreuil K, et al. Mutations in EOGT confirm the genetic heterogeneity of autosomal-recessive Adams-Oliver syndrome. Am J Hum Genet 2013 Apr 4;92(4):598–604.
4. Shaheen R, Faqeih E, Sunker A, et al. Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome. Am J Hum Genet 2011 Aug 12;89(2):328–33.
5. Southgate L, Machado RD, Snape KM, et al. Gain-of-function mutations of ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis aplasia and limb anomalies. Am J Hum Genet 2011 May 13;88(5):574–85.
6. Ru Y, Liu G, Bai J, Dong S, Nie N, Zhang H, et al. Congenital dyserythropoietic anemia in China: a case report from two families and a review. Ann Hematol 2013 Nov 7.
7. Sutton VR, Plunkett K, Dang DX, Lewis RA, Bree AF, Bacino CA. Craniofacial and anthropometric phenotype in ankyloblepharon–ectodermal defects–cleft lip/palate syndrome (Hay–Wells syndrome) in a cohort of 17 patients. Am J Med Genet A 2009 Sep;149A(9):1916–21.
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Pachyonychia congenita

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3. Eliason MJ, Leachman SA, Feng BJ, Schwartz ME, Hansen CD. A review of the clinical phenotype of 254 patients with genetically confirmed pachyonychia congenita. J Am Acad Dermatol 2012; Jan 18.
4. Akasaka E, Nakano H, Nakano A, et al. Diffuse and focal palmoplantar keratoderma can be caused by a keratin 6c mutation. Br J Dermatol 2011;165(6):1290–2.
5. Wilson NJ, Messenger AG, Leachman SA, et al. Keratin K6c mutations cause focal palmoplantar keratoderma. J Invest Dermatol [Research Support, Non-US Gov't]. 2010;130(2):425–9.
6. Spaunhurst KM, Hogendorf AM, Smith FJ, et al. Pachyonychia congenita patients with mutations in KRT6A have more extensive disease compared with patients who have mutations in KRT16. Br J Dermatol [Research Support, Non-US Gov't]. 2012;166(4):875–8.
7. Du ZF, Xu CM, Zhao Y, et al. Two novel de novo mutations of KRT6A and KRT16 genes in two Chinese pachyonychia congenita pedigrees with fissured tongue or diffuse plantar keratoderma. Eur J Dermatol 2012;22(4):476–80.
8. Harris K, Hull PR, Hansen CD, et al. Transgrediens pachyonychia congenita (PC): case series of a nonclassical PC presentation. Br J Dermatol 2012;166(1):124–8.
9. Goldberg I, Sprecher E, Schwartz ME, Gaitini D. Comparative study of high-resolution multifrequency ultrasound of the plantar skin in patients with various types of hereditary palmoplantar keratoderma. Dermatology 2013;226(4):365–70.
10. Wilson NJ, Perez ML, Vahlquist A, et al. Homozygous dominant missense mutation in keratin 17 leads to alopecia in addition to severe pachyonychia congenita. J Invest Dermatol 2012;132(7):1921–4.
11. Naz G, Pasternack SM, Perrin C, et al. FZD6 encoding the Wnt receptor frizzled 6 is mutated in autosomal-recessive nail dysplasia. Br J Dermatol 2012;166(5):1088–94.
12. Frojmark AS, Schuster J, Sobol M, et al. Mutations in Frizzled 6 cause isolated autosomal-recessive nail dysplasia. Am J Hum Genet 2011;10;88(6):852–60.
13. Goldberg I, Fruchter D, Meilick A, Schwartz ME, Sprecher E. Best treatment practices for pachyonychia congenita. J Eur Acad Dermatol Venereol. 2014;28(3)279–85.
14. Swartling C, Karlqvist M, Hymnelius K, Weis J, Vahlquist A. Botulinum toxin in the treatment of sweat-worsened foot problems in patients with epidermolysis bullosa simplex and pachyonychia congenita. Br J Dermatol 2010;163(5):1072–6.
15. Gruber R, Edlinger M, Kaspar RL, et al. An appraisal of oral retinoids in the treatment of pachyonychia congenita. J Am Acad Dermatol 2012;66(6):e193–9.
16. Hickerson RP, Leake D, Pho LN, Leachman SA, Kaspar RL. Rapamycin selectively inhibits expression of an inducible keratin (K6a) in human keratinocytes and improves symptoms in pachyonychia congenita patients. J Dermatol Sci 2009;56(2):82–8.
17. Zhao Y, Gartner U, Smith FJ, McLean WH. Statins downregulate K6a promoter activity: a possible therapeutic avenue for pachyonychia congenita. J Invest Dermatol 2011;131(5):1045–52.
18. Leachman SA, Hickerson RP, Schwartz ME, et al. First-in-human mutation-targeted siRNA phase Ib trial of an inherited skin disorder. Mol Ther 2010;18(2):442–6.
19. Hickerson RP, Flores MA, Leake D, et al. Use of self-delivery siRNAs to inhibit gene expression in an organotypic pachyonychia congenita model. J Invest Dermatol 2011;131(5):1037–44.

Dyskeratosis congenita

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Nail–patella syndrome

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Hereditary anonychia

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3. Ishii Y, Wajid M, Bazzi H, et al. Mutations in R-spondin 4 (RSPO4) underlie inherited anonychia. J Invest Dermatol 2008;128(4):867–70.