This document discusses genodermatosis, which are inherited skin disorders caused by a genetic alteration. It focuses on neurofibromatosis type 1 (NF1), describing its genetics, clinical features, diagnostic criteria, course, and treatment. NF1 is caused by a mutation in the NF1 gene and is characterized by café-au-lait macules, neurofibromas, Lisch nodules, and other features. Diagnosis requires two or more criteria including 6 CALMs or family history. Treatment focuses on symptoms like surgically removing tumors; the condition has variable progression.

1. GENODERMATOSIS
Dr. Arushi Jain

2.  INHERITED SKIN DISORDERS WHICH REQUIRE AN
ALTERATION IN THE FUNCTION OF A GENE(SINGLE
GENE DISORDERS) ARE CALLED GENODERMATOSIS.
1) Inherited immunobullous disorders
2) Disorders of keratinization
3) Hereditary disorders of pigmentation
4) Familial multiple tumor syndromes
5) Ectodermal dysplasias
6) Syndromes associated with genomic instability
7) Poikilodermatous disorders
8) Connective tissue disorders
9) Vascular & lymphatic disorders
10) Porphyrias
11) Disorders associated with immunodeficiency

5. FAMILIAL MULTIPLE
TUMORS SYNDROME

6. NEUROFIBROMATOSIS
 Characterized by neurofibroma & café au lait
macules(CALM),associated with other cutaneous and
systemic manifestations.
 Classification(RICCARDI)-

7. NEUROFIBROMATOSIS 1

8. NEUROFIBROMATOSIS 1
 1 per 2500-3300 births.
GENETICS
 AD inheritance
 Gene located on 17q11.2 which encodes for protein
neurofibromin.
 It is a tumor suppressor gene & regulates the
inactivation of the ras proto-oncogene which is
involved in cell proliferation, differentiation and
learning.
 Variable expressivity & manifestations are more severe
when inherited from the mother.

9. CLINICAL FEATURES
 CUTANEOUS FEATURES-
 NEUROFIBROMAS-
 Benign nerve sheath tumors, soft, lilac-pink, sessile & dome
shaped,sometimes pedunculated with button-hole feeling on
digital pressure.
 Site - trunk and limbs ranging from few mm to several cms. In
women they are prominent on areola of the breast. increase in
number during puberty & pregnancy.
 PLEXIFORM NEUROFIBROMA-diffuse elongated fibroma
commonly seen along the branches of trigeminal and cervical
nerves with a wormy sensation involving 1/multiple nerve
fascicles from branches of nerves.
 Complication- malignant peripheral nerve sheath tumors.

11. CLINICAL FEATURES
 CALM-well circumscribed,light-brown patches,varying from
0.5-50cm seen in 90% of cases.
 Present at birth or appear as the 1st lesion.
 Increase in size & number throughout the 1st decade.
 Number is not indicative of clinical severity.
 Represent collection of heavily pigmented melanoctyes.
 FRECKLES-occur in 70% cases.
 CALMS<5 mm
 Site -axillae, groin, under breasts. when it is virtually
pathognomonic(CROWE’S SIGN)(not related to sun
exposure).
 Darker pigmented patches over a plexiform
neurofibroma,extending to the midline of the spine indicates
that tumor involves spinal cord.

13.  MUCOSAL FEATURES
 Papillomatous tumors involving palate,buccal mucosa and lips
observed in 5-10% of cases.U/L macroglossia may be seen.
 OCULAR FEATURES
 LISCH NODULES-pigmented, slightly raised iris
hamartomas that occur in 90% of affected adults.
 Seen with a slit lamp, no impairment of vision.
 Asymptomatic but increase with age. Do not occur in segmental
or bilateral acoustic NF.

15.  SKELETAL FEATURES
 Kyphoscoliosis(2%)
 Asymptomatic Pseudoarthrosis of tibia or radius(1%)
 Sphenoid wing dysplasia(characteristic abnormality)
 Short stature, dysplasia of long bone thinning-m/c tibia
 Osteoporosis(loss of function of neurofibromin)
 Optic pathway tumors
 Optic nerve glioma, astrocytoma, schwannoma
 Chiasmal tumors
 c/o visual loss, rapid onset of proptosis
 ASSOCIATED MALIGNANCIES-leukemias,wilm’s
tumor, rhabdomyosarcoma, retinoblastoma, pheochromocytoma,
CML, ALL,

16.  ENDOCRINE MANIFESTATIONS
 Precocious puberty
 Gynecomastia
 Hyperparathyroidism
 Acromegaly
 Addison’s disease
 pheochromocytoma

17. DIAGNOSTIC CRITERIA FOR NF1
Presence of 2 or more are needed for diagnosis :
1. 6 or more CALMs, >5mm in prepubertal &
>15mm in adults.
2. 2 or more NF or 1 plexiform NF
3. Axillary or inguinal freckling
4. Optic glioma
5. 2 or more lisch nodules
6. Distinctive osseous lesion-sphenoid dysplasia/ thinning of
cortex of long bones with or without pseudoarthrosis.
7. First degree relative(parent,sibling,offspring) with NF1 by
above criteria.

18. COURSE AND PROGNOSIS
 Variable and unpredictable course.
 Poor prognosis-early onset,rapid progression before
puberty,extensive systemic involvement
 Enlargement and pain in lesions indicative of
haemorrhage or malignant change.
 Sarcomatous changes within a single or multiple
neurofibromas(1.5-15%)
 Reduced life expectancy due to development of
malignancy & other complications like
hypertension(pheochromocytoma or Renal artery
stenosis)

19. DIAGNOSIS
 Mainly clinical-thorough examination of patient & family
members.
 HPE of neurofibroma-distinctive; shows arborising schwann
cells and collagenous stroma
 Slit lamp examination of eye
 Skeletal survey
 CT & MRI for neurological screening-intraspinal lesions show
“dumbbell appearance”
 Prenatal diagnosis(>95% accuracy except in de novo
mutations)
 DIFFERENTIAL DIAGNOSIS-CALMs are present in:
a) 10-20% of normal individuals
b) Tuberous sclerosis, bloom syndrome, fanconi’s anaemia
c) McCune-Albright syndrome, cowden’s disease

20. TREATMENT
 Symptomatic mainly
 Large,disfiguring,rapidly progressive & painful
lesions can be excised
 CALMS- Laser therapy
 NF – surgical removal, chemo therapy under trial
 OPT – chemotherapy with carboplatin, vincristine
 Surgical debulking of plexiform lesions

22. NEUROFIROMATOSIS 2
 BILATERAL ACOUSTIC SCHWANNOMA
 Characterised by B/L vestibular schwannomas, meningiomas
& other CNS tumors
 AD ;gene on chromosome 22q11.21 (tumor suppressor gene)
 Chromosome 22 encodes for schwannomin (neurofibromin2,
merlin)
 CUTANEOUS LESIONS- cutaneous schwannoma- plaque like
raised lesion with a faint violet hue confused with cutaneous nf &
CALM
 CALMs are large & pale
 VESTIBULAR LESIONS-manifest as
tinnitus,vertigo,deafness(3rd decade)
 Juvenile posterior subcapsular cataract common

24. SEGMENTAL
NEUROFIBROMATOSIS
 Somatic mosaicism of NF1 gene-post zygotic mutation of NF1
gene.
 Cutaneous neurofibroma,CALM & freckling localised to 1
area of the body.
 Isolated plexiform neurofibroma or tibial pseudoarthrosis may
represent segmental NF.
 Full blown disorder may manifest in next generation,this
has to be conveyed during genetic counselling.

26. TUBEROUS SCLEROSIS
COMPLEX
SYN.:
BOURNEVILLE’S DISEASE,
EPILOIA

27. GENETICS
 Multisystem hamartomatous tumours involving
skin,eye,CNS,heart,lungs,kidneys and bones.
 Incidence-1 in 6,000.
 M=F
 AD inheritance with variable expressivity.
 Mutation of 2 genes-TSC1(9q34) and TSC2(16p13).
 TSC1 & TSC2 encode hamartin and tuberin respectively.
 Sporadic cases occur mostly due to TSC2 mutations.
 TSC2 gene found close to PCKD gene.

28. Facial angiofibromas
ash leaf spots
hypomelanotic macules
confetti lesions
shagreen patch
fibrotic plaque
ungual fibromas
non specific findings
Cutaneous features

29. CUTANEOUS FEATURES
 CUTANEOUS ANGIOFIBROMAS(ADENOMA
SEBACEUM)
 Usually appear at 3-4 years(birth-3rd decade).
 1-3mm, reddish pink papules distributed symmetrically over
nasolabial folds,cheeks,chin;sometimes on
eyelids,forehead,ears & scalp.
 More extensive during puberty, erythema increases by emotion
and heat.
 U/L angiofibroma-in mosiac form.
 ASH-LEAF SPOTS
 1-3cm,lanceolate,hypopigmented macules
 Site – buttocks, trunk
 Seen in 90% of affected individuals.

30.  Either present at birth or appear in infancy.
 May 1-20 in number.
 Visualized easily by Woods lamp in fair skinned.
 SHAGREEN PATCH(PEAU DE CHAGRINE)
 50% of patients. Present at infancy or develop later
 Appear concurrently with angiofibromas.
 Skin colored, pink, brown, papules and nodules-firm,
rubbery irregular plaques ranging from 1-10 cm
 Solitary or multiple.
 Site : lumbosacral region,back, buttocks, thighs.

31.  CONFETTI-LIKE LESIONS
 Numerous,2-3mm in size,white spots.
 Symmetrically distributed on extremities(legs,
forearms)
 More common after 10 yrs of age.
 FIBROTIC PLAQUE/NODULE
 Seen on forehead commonly.
 Site- cheek or scalp(whole face)
 Congenital or gradually over the years
 Skin colored or red, hyperpigmented,firm and maybe
large.

32.  KOENEN’S TUMORS
 Periungual or subungual fibromas.
 1mm to 1 cm, smooth, skin colored, red, firm soft rounded
papules and nodules arising from under the nail plate or
proximal nail fold.
 m/c in toes than fingers.
 Appear after first decade.
 NON SPECIFIC FINDINGS
 Soft,penduculated fibromas around the neck- military
fibromas.
 Molluscum fibrosum
 Poliosis of eyelash & scalp hair.
 Gingival fibroma, overgrowth, dental pitting

33. ADENOMA SEBACEUM

34. ASH LEAF MACULES

35. SHAGREEN PATCH

36. KOENEN’S TUMOR

37. GINGIVAL FIBROMA

38. OCULAR FEATURES
 RETINAL HAMARTOMAS-seen in 50-76%
cases;
Present as flat,gray/yellow streaks along blood
vessels or elevated,multinodular lesions resembling
mulberries.
usually asymptomatic but may give rise to
scotomas.
 strabismus, colobomas, angiofibromas of eyelids
 White spots in iris or retina analogous to ash- leaf
spots in the skin.

39.  CNS FEATURES
 Subependymal nodules(tubers), cortical tubers,
subependymal giant cell astrocytomas.
 They may be calcified.
 Seizures,mental retardation,obstructive
hydrocephalus,behaviour disorders and psychotic
symptoms.
 CARDIAC LESIONS
 Rhabdomyomas occur during infancy(50%).
 Cardiac arrythmias and sudden cardiac death may occur.

40.  RENAL LESIONS(15%)
 Most common is angiomyolipoma,usually
asymptomatic.
 B/L multiple renal cysts(due to close proximity of TSC2
and PKD1 on chromosome 16).
 Malignant angiomyolipoma,Renal cell
carcinoma
 PULMONARY LESIONS
 Multifocal,micronodular pneumocyte
hyperplasia.
 Spontaneous pneumothorax(2nd decade).
 Pulmonary lymphangioleiomyoma

41. DIAGNOSTIC
CRITERIA
FOR TS

42. DIAGNOSIS
 DEFINITE DIAGNOSIS-2major or 1 major+2 minor
 PROBABLE DIAGNOSIS-1 major+1 minor
 POSSIBLE DIAGNOSIS-either 1 major or 2 or
more minor
 INVESTIGATIONS
 Woods lamp examination for ash leaf macules
 Ophthalmoscopic examination
 CT/MRI of brain(calcified periventricular nodules & cortical
tubers)
 Neonatal 2-d echo for rhabdomyoma
 Calcification in skull X ray(50% in older patients)
 Abdominal USG/CT-for renal lesions
 X ray hand & feet-cystic lesions of phalanges

43. ENHANCING SUB EPENDYMAL NODULES

44. ATRIAL RHABDOMYOMA ON
CARDIAC CT

45. COURSE AND PROGNOSIS
 Common causes of death are seizures,intracranial
tumors,pulmonary fibrosis or cardiac failure.
 Prognosis depends on severity of disorder.
 Life expectancy for severely affected is poor-
infant and childhood death rate 3% and 28%
respectively.
 In adulthood 75% die before 1st quarter of life .

46. TREATMENT
 Counselling
 For skin tumors- surgical resection.
 Neurosurgical intervention for obstructive hydrocephalus.
 Microsurgical removal of brain neoplasms.
 Angiofibroma removed by curettage, chemical peel,
cryosurgery, dermabrasion, electrosurgery, pulsed dye
vascular laser or carbon dioxide laser.

47.  Ungual fibroma- excision
 Shagreen patch- left untreated or excised.
Rapamycin(sirolimus),an immunosuppressant has been
found to be effective-can induce regression of brain
astrocytoma.

50. Poikilodermatous
disorders
Dyskeratosis congenita

51. Dyskeratosis congenita
• Syn Zinsser- cole-engmann syndrome
• Rare, multisystem disorder characterised by –
poikiloderma, nail dystrophy, leukoplakia, bone marrow
aplasia and predisposition to malignancy.
• m/c in males
• Genetics – XLR( but AD and AR patterns also seen )
• Missense mutation in DKC1 gene located on Xq28 which
ncodes for protein dyskerin and its function is imp for
nucleolar function and cell cycle.
• Other gene mutations – NHP2, NOP10, TERC
• Chromosomal instability & impaired DNA repair
predisposes to malignancy.
• Nail +skin +mucous membrane all present.

52. Nail changes-
• Thinning, grooving
• Pterygium
• Dystrophic changes
• Complete destruction by 5-13 years of age
• Suppurative paronychia-recurrent

53. Cutaneous-
pigmentation – fine, reticulate, gray brown skin
pigmentation.
site – neck,upper chest, arm, thighs, trunk.
Telangiectasias & atrophy over pigmented areas to give rise
to full picture of poikiloderma
skin over face, hands, feet atrophic shiny looking
PPKD with loss of dermatoglyphic markings &
hyperhidrosis.
Hair dry, sparse, premature greying

54. Mucosal
tongue and buccal membranes involved
vesicles then leukoplakic patches
eyelid scarring
anorectal & urethral leukoplakia
oesophageal stricture
conjunctival involvement
bone marrow aplasia, refractory anemia,
pancytopenia, neutropenia
haematologic Hodgkin’s disease, physical &
mental retardation.

55. Diagnosis –
nail dystrophy, poikiloderma, mucosal leukoplakia-
triad
histopathology-
epidermis atrophy, increased vascularity of dermis
with sparse lymphocytic infiltrate, pigment laden
macrophages.
d/d –Rothmund Thomson syndrome as
poikilodermatous changes.

57. Treatment
monitoring of blood count levels
follow up of leukoplakia
systemic retinoids for regression of leukoplakia
GCSF for bone marrow aplasia
allogenic BM transplant

58. SYNDROMES
ASSOCIATED WITH
GENOMIC INSTABILITY
XERODERMA PIGMENTOSUM

59. XERODERMA PIGMENTOSUM
 It’s a disorder with photosensitivity,
oculocutaneous pigmentation , and early neoplasia
resulting from abnormal DNA repair.
INCIDENCE
 Relatively common in countries with custom of
consanguinity.
 Seen in 1 in 2,50,000 birth in Europe & USA.

60. SUBTYPES
 Seven subtypes (complementation groups A-G)
and a variant – XP-V is known.
 XP-C is the most common subtype worldwide .
 XP-A is most common in Japan, but also seen in
other parts of Asia, Europe and USA.
 XP-D and XP-F are of intermediate occurrence.
 XP-B, E and G sub types are extremely rare.

61. GENETICS
 The inheritance pattern is AR.
 Parents are obligate heterozygotes without any
clinical manifestations.
 Genes responsible for each subtype are as
follows – XPA (9q22.3) , XPB (2q21) , XPC
(3p25) , XPD (19q13.2-13.3) , XPE (11p12-p11)
, XPF (16p13.3-13.13) , XPG (13q33).
 A form of XP with AD inheritance pattern also
exists.

62. PATHOGENESIS
 There is a defect in the nucleotide excision repair
(NER) pathway, responsible for the removal and
replacement of damaged DNA.
 This results in diminished DNA repair in the cells
exposed to the UVB range of sunlight.
 This explains the photosensitivity and carcinogenesis
observed in patients with XP.

63. CLINICAL FEATURES
1. CUTANEOUS
 These features appear early.
 Affected children maybe normal at birth but develop
persistent erythema, acute sun-burn, xerosis, and
diffuse freckling of photo-exposed body parts
6months- 3years of age.
 Freckles are pin point to 1cm in size, dark brown,
progressive and permanent.
 With time, conjunctiva, lips and covered body parts
are also involved.

66.  Associated numerous atrophic hypopigmented
macules give rise to a mottled appearance.
 Multiple telengiectasias are present
interspersed among the freckles.
 Acute sun exposure gives rise to vesiculation,
ulceration, crusting and atrophic scarring.
This tendency minimizes with age.
 Pre malignant lesions like keratoacanthoma
and actinic keratoses are common.
 BCC may appear as early as third or fourth
year of life.
 Other common malignancies are SCC and
malignant melonoma.

67. MALIGNANT MELANOMA INXP

68.  Rarely, angiosarcoma and fibrosarcoma may
occur.
 Buccal mucosal and glossal telengiectasias,
leukoplakia and SCC of the anterior tongue
are common.
2. OCULAR
 Present in 80% patients.
 Include photophobia, conjunctival xerosis,
and recurrent conjunctivitis in the early
months of life.
 Gradually freckle-like pigmented macules
appear in the bulbar conjuctiva.

69.  Acute episode of photodamage gives rise to
scarring of the eyelids, loss of eyelashes,
symblepheron, and ectropion.
 Other changes include vascular pterygium,
corneal opacities, ocular keratoacanthoma,
and epithilioma of eyelids.
3. NEUROLOGICAL
 20% patients.
 Includes mental retardation, areflexia
/hyporeflexia, spasticity, ataxia and SNHL.
 These start manifesting in early infancy,
upto 2nd decade.

70. 4. SYSTEMIC MALIGNANCIES
 10 to 20 fold higher incidence.
 Include medulloblastoma and astrocytoma of
brain, bronchogenic, gastric, pancreatic,
uterine, testicular and breast carcinomas.
5. METABOLIC AND BIOCHEMICAL
ABNORMALITIES
 Aminoaciduria, hypoglycemia and adrenal
hypofunction may occur.
6. IMMUNE DYSFUNCTION
 Abnormal susceptibility to infections may be
present.

71. 7. ASSOCIATIONS
 Systemic lupus erythematosus
 Cockayne syndrome
 In general, cutaneous manifestations are
severe in XPA, XPC, XPD and XPG.
 Neurological manifestations are seen mostly
among XPA and XPD, occasionally among
XPC and XPG.
 Clinical features are mild in XPE and XPF.
 Autosomal dominant variants have a milder
clinical course.

72. DIAGNOSIS
 Photosensitivity, freckled skin, and
photophobia are quite characteristic of
the disorder.
 No specific change in histopathological
examination of skin in initial stages.
 In advanced cases, there is flattening of
epidermis with a distinctive irregular
proliferation of rete pegs, heavily laden with
pigments.
 Basophilic degeneration of dermal collagen,
features of solar elastosis, and increased
vascularity are seen.

73.  Demonstration of DNA repair defect is
confirmatory. The unscheduled DNA
synthesis (UDS) assay following UV-
irradiation of skin fibroblasts, lymphocytes
or epidermal cells in culture is the standard
diagnostic method.
 DNA repair defects are also demonstrable in
amniotic fluid cells; this helps in prenatal
diagnosis of XP.

74. DIFFERENTIAL DIAGNOSIS
 Bloom syndrome
 Cockayne syndrome
 Rothmund- thompson syndrome
 Erythropoetic porphyria
 Hartnup disease
Freckles are distinctive feature of XP and
differentiate it from other causes of childhood
photosensitivity mentioned above.

75. COURSE AND PROGNOSIS
 There are no means to prevent freckling or the
occurrence of malignancies except avoidance of
sun exposure.
 Early death results from metastatic
malignancies.
 Two thirds patients die before the age of
20years.
 Other causes of morbidity and mortality are
recurrent infections and neurological
complications.

76. TREATMENT
 Strict photoprotection – Using physical
sunscreens and UV blocking garments, lip balms.
Modification of lifestyle and change of work
schedules can be done to prevent exposure to
sunlight.
 Regular medical supervision – For early
detection of premalignant and malignant lesions
of skin and mucosa. Such lesions should be
managed promptly by modalities like topical 5-
FU, cryotherapy, dermabrasion, excision and
grafting or intralesional IFN alpha.

77.  Ophthalmic care – Use of sunglasses with side
shields, artificial tears, soft contact lenses, and
corneal transplants.
 Oral isotretinoin (1mg/kg body weight) can
reduce the incidence of cutaneous
malignancies in patients with XP.
 A new therapeutic modality is topical
application of liposomal lotion of the
microbial enzyme T4 endonucleaseV. This
enzyme helps the affected cells to bypass the
DNA repair defect and is thus useful in reducing
the incidence of actinic keratosis and basal cell
carcinoma.

78. Prophylactic measures:
Avoid cigarette smoking( α pyrene is a UV
mimetic)
Avoid environmental carcinogens

79. DE SANCTIS- CACCHIONE SYNDROME
 The patients have classical cutaneous and ocular
features of XP plus some distinct features like
microcephaly, dwarfism, severe mental
retardation, deafness, hypogonadism,
shortening of tendo Achilles, and
neurological features like choreoathetosis
and cerebellar ataxia.
 The extreme manifestations of this entity are seen
in association with XP-A.
 The pathological defect is the loss of
neurons in the cerebral cortex and
cerebellum without any obvious
inflammation.

80. COCKAYN’S SYNDROME
 Photosensitivity
 Typical facial features – deep set eyes,
loss of sc fat, pigmentary retinal
degeneration, post natal growth
failure, snhl, neuro degenerations.
 Mickey mouse like facies.
 No increased incidence of malignancy
 Follows AR inheritance pattern.
 P/G – DNA repair defect in the transcription-
coupled repair (TCR) pathway.

81. BLOOM SYNDROME
• Photosensitivity
• Malar erythema,
• Calms
• AR
• Immune ddeficiency, growth retardation,
unusual facies, male infertility and female
subfertility, type 2 Dm
• Most cancers types- leukemia, lymphomas,
carcinomas of breast & git.
• Facies- narrow shaped.

82. ROTHMUND THOMSON SYNDROME
• Photosensitivity, poikiloderma, alopecia
• Skeletal abnormalities
• growth deficiencies
• juvenile cataracts
• osteoporosis
• Malignancies like – osteosarcomas, cutaneous
SCC and others
• Bird like facies.

83. Trichothiodystrophy
• Photosensitivity
• Brittle hair
• Ichthyosis
• Collodion membrane
• Tiger tail banding of hair with polarised
microscopy
• Congenital cataracts, short stature,
microcephaly.

84. Ataxia telangiectasia
• Telangiectasias
• Progressive cerebellar ataxia
• Immune defects
• Hypogonadism
• T cell leukemias,
• Acute toxicity of therapeutic x rays.

85. GENETIC COUNSELLING
 Process of communication and education that addresses
concerns relating to the development and/transmission of
a hereditary disorder.
 Provided to couples with a family h/o or h/o of earlier
childbirth with genodermatosis.
 Steps include-
a) Establishment of diagnosis
b) Assessment of risk
c) Communication with the couple
d) Discussion of options
e) Longterm contact & support
 Couples should be explained mode of
inheritance,possibility of proportion of children
affected,risk of transmission to next generations,grades
of severity of disorder & prognosis.

86. GENETIC COUNSELLING
 It is essential to establish a diagrammatic
representation of family pedigree.
 Consanguinity is a relationship between blood
relatives who have at least one ancestor in
common,no more remote than a great great
grandparent.
 For AR disorders,consanguinity increases the
proportion of homozygosity.
 For offsprings of first cousins,risk of congenital
malformation is 2.5 times more than children
with unrelated parents.