ECTODERMAL DYSPLASIA

ECTODERMAL DYSPLASIA

1. ECTODERMAL DYSPLASIA Dr. Yugandar

2. ectodermal dysplasias is of a group of inherited disorders that share in common developmental abnormalities of two or more of the following: hair, teeth, nails, sweat glands and other ectodermal structures like mammary gland, thyroid gland, thymus, anterior pituitary, adrenal medulla, central nervous system, external ear,melanocytes , cornea, conjunctiva, lacrimal gland and lacrimal duct.

3. One definite benefit is that the problems encountered by many patients and families are grouped regardless of the specific subtype of ED & Parents and children can benefit by being part of larger support networks exemplified by the Ectodermal Dysplasia Society http://www.ectodermaldysplasia.org the National Foundation for Ectodermal Dysplasias http://www.nfed.org

4. Many conditions encompassed by this broad definition are not usually considered as primarily ED incontinentia pigmenti , dyskeratosis congenita, trichothiodystrophies , Cardio facio cutaneous syndrome, pachyonychia congenita & Goltz syndrome By Definition they are ED, but common practice has been to consider many of these as separate entities ’

5. The first clinical cases with features of ED were reported as early as 1792, when Danz described two Jewish boys with congenital absence of hair and teeth In 1875 Charles Darwin reported the case communicated to him by a Mr. Wedderburn , Hindoo family in Scinde in which ten men, in the course of four generations, in their both jaws taken together, with only four small and weak incisor teeth and with eight posterior molars This family would have X-linked hypohidrotic ectodermal dysplasia

6. small series of cases with hypotrichosis , hypodontia , onychodysplasia and anhidrosis had been described under various names such as dystrophy of hair and nails imperfect development of skin, hair and teeth congenital ectodermal defect term ‘ ectodermal dysplasia’ appear 1929 Touraine suggested ‘ ectodermal polydysplasia ’

7. Weech specified three essential aspects of ectodermal dysplasias : most of the disturbances must affect tissues of ectodermal origin these disturbances must be developmental heredity plays a causal role

8. ECTODERM Ectoderm is one of the three primary germ cell layers in the very early embryo The other two layers are the mesoderm (middle layer) and endoderm , with the ectoderm as the most exterior layer It emerges and originates from the outer layer of germ cells The word ectoderm comes from the Greek ektos meaning "outside", and derma, meaning "skin."

9. Ectoderm differentiates to form the nervous system (spine, peripheral nerves and brain), tooth enamel and the epidermis It also forms the lining of mouth, anus, nostrils, sweat glands, hair and nails In vertebrates, the ectoderm has three parts: external ectoderm (also known as surface ectoderm), the neural crest, and neural tube the latter two are known as neuroectoderm

10. 1.Pre aortic ganglion 2.Sympathetic ganglion 3.Organ plexus 4.Suprarenal gland 5.Dorsal root ganglion 6.Surface ectoderm 7.Neural tube 8.Dorsal aorta 9.Urogenital ridge 10.Notochord

11. What is the cause of ectodermal dysplasia? mutation or deletion of certain genes located on different chromosomes. ED s are caused by a genetic defect they may be inherited or passed on down the family line. In some cases, they can occur in people without a family history of the condition, in which case a de novo mutation has occurred.

12. Connexin defects : Gap junctions are intercellular channels that connect the cytoplasm of neighbouring cells, Facilitating cellular growth, differentiation,tissue morphogenesis, homeostasis Transmembrane connexin proteins undergo oligomerization to form the connexons that compose Gap junctions

13. In the Golgi network six connexin subunits assemble to form a connexon The connexon is then transported to the plasma membrane. Other connexons then coaggregate to form homotypic or heterotypic gap junctions.

14. Cx26, Cx30, Cx31 and Cx43 expressed in ectoderm-derived epithelia of the inner ear and cornea as well as in the epidermis and its appendages Connexin defects a/f the sensorineural deafness, keratitis and cutaneous abnormalities (ranging from keratoderma to erythro keratoderma to ectodermal dysplasias affecting the hair and nails)

15. Genetics   Are the ectodermal dysplasias hereditary? The ED are caused by alterations in genes Altered genes may be inherited from a parent Normal genes may become altered (mutate) at the time of egg or sperm formation or after fertilization Chances for parents to have affected children depend on the inheritance pattern of the type of ectodermal dysplasia

16. How Inheritance Works   New Mutation: Generally, when a mutation has occurred, there is little chance that it will occur in another child of the same parents The affected child may transmit the trait

17. Autosomal Dominant : When the ED is an autosomal dominant trait, the parent who is affected has a single copy of the abnormal gene and may pass it on to his or her children Regardless of the gender of the parent or the child, there is a 50% chance for each child All children who receive the abnormal gene will be affected

18. Autosomal Recessive When the ectodermal dysplasia in the family is an autosomal recessive trait, the usual situation is that each parent is unaffected The parents are said to be carriers They each have a single copy of the abnormal gene the chance for them to have another affected child is 1 in 4 1 in 4 children get a copy of the abnormal gene from each parent and is affected 2 in 4 gets only one copy each and are carriers the remaining 1 in 4 inherits a normal gene from each parent and is not affected

19. X-Linked Recessive If a woman is a carrier of an X-linked recessive disorder there is a 50% chance that each male child will receive the abnormal gene and be affected 50% chance that each female will receive the abnormal gene and be a carrier (like the mother).  If a man has the abnormal gene he is affected and will pass the gene on to all of his daughters. The daughters will be carriers Since the gene is on the X chromosome, sons will not be affected because they receive the mans Y chromosome

20. Freire -Maia and Pinheiro classification depend on clinical phenotypes & inheritance patterns of ED designated conditions by groups depending on presence of hair, nail, tooth or sweat gland abnormalities conditions that had involvement of hair (1), teeth (2), nails (3) ,sweat glands (4),other ectodermal (5)

21. Classification: molecular approaches Plays important insights into the molecular basis of the ED the molecular data have confirmed clinical impressions, Eg: Hay–Wells syndrome and ectrodactyly , ectodermal dysplasia, clefting (EEC) syndrome

22. Classification: Genetic mechanisms ED due to mutations in tumour necrosis factor (TNF)-like/NF- κB signalling pathways, the p63-related ED ED due to other transcription factors ED due to mutations in gap junction proteins.

23. In an attempt to classify these, different subgroups are created according to the presence or absence of 4 primary ED defects:  ED1: Trichodysplasia (hair dysplasia) ED2: Dental dysplasia ED3: Onychodysplasia (nail dysplasia) ED4: Dyshidrosis (sweat gland dysplasia)

24. Eds are categorised into one of the following subgroups made up from the primary ED defects  Subgroup 1-2-3-4 Subgroup 1-2-3 Subgroup 1-2-4 Subgroup 1-2 Subgroup 1-3 Subgroup 1-4 Subgroup 2-3-4 Subgroup 2-3 Subgroup 2-4 Subgroup 3 Subgroup 4

25. In 2001 , Priolo and Lagan à reclassified the ectodermal dysplasias into 2 main functional groups: (1) defects in developmental regulation/epithelial- mesenchymal interaction (2) defects in cytoskeleton maintenance and cell stability.

26. In 2003, Lamartine reclassified ED into the following 4 functional groups based on the underlying pathophysiologic defect: (1) cell-to-cell communication and signaling (2) adhesion (3) development (4) other

27. The most common ectodermal dysplasias Hypohidrotic ED which falls under subgroup 1-2-3-4 Hidrotic ED which comes under subgroup 1-2-3.

28. The three most recognised ED syndromes fall into the subgroup 1-2-3-4 they show features from all four of the primary ED defects  Ectrodactyly -ED- clefting syndrome Rapp-Hodgkin hypohidrotic ED Ankyloblepharon , ectodermal defects, cleft lip/palate (AEC) or Hay-Wells syndrome

29. Hypohidrotic ectodermal dysplasia X-linked HED is the most common of ED Charles Darwin described it first,Later by Christ, Siemens & Touraine characterized by hypotrichosis hypodontia , hypohidrosis

30. Majority are X-L-R inheritance involved gene ED- 1,located on Ch X-q12-13.1. Encodes a protien ECTODYSPLASIN A ,member of TNF family

31. AD & AR inheritance can occur Autosomal gene has been mapped to Ch 2q 11-q1 (ED 3 ) CRINKLED gene identified – AR HED Autosomal recessive HED is clinically identical to X-linked HED females are as severely affected as males

32. PATHOPHYSILOGY : Mutations in the EDA, EDAR, and EDARADD genes cause HED The EDA, EDAR & EDARADD genes provide instructions for making proteins These proteins form part of a signaling pathway that is critical for the interaction between two cell layers, the ectoderm and the mesoderm

33. CLINICAL FEATURES Hair: Scalp hair is sparse, fine, lightly pigmented and grows slowly Eyebrows & eyelashes are scanty or absent Secondary sexual hair in the beard, pubic and axillary regions is variably present and may be normal Hair on the torso and extremities is usually absent

34. Teeth: Both deciduous and permanent teeth are affected The alveolar ridges are hypoplastic missing teeth or retarded growth of teeth peg-shaped Tooth enamel is also defective Dental treatment is necessary & children as young as 2 years may need dentures

35. Conical teeth

36. Upper Incisors have been resorted Orthopantogram shows absence of 10 Primary & 11 Permanent teeth

37. Nails : N ails are normal in most individuals Sweat glands: Sweating is severely diminished or absent due to a paucity or absence of eccrine glands An absence of sweating leads to an inability to thermoregulate

38. Thermoregulation is most problematic in infants and young children, may recurrent bouts of fever as high as 42°C Heat intolerance can occur in older children and adults

39. Skin: At birth, affected males may demonstrate marked scaling or peeling of their skin skin is fine, smooth and dry in adults Peri orbital hyperpigmentation fine wrinkling around the eyes

40. Eczema is common and is prominent in flexural areas Small milia like papules may be found on the face Diminished or absent salivary glands & mucous glands of the nose, mouth and ears cause nasal obstruction by thick, fetid nasal discharge & adherent nasal crusts, sinusitis recurrent upper respiratory tract infections

41. Diminished production of tear film from the lacrimal glands cause dry eyes, photophobia & corneal damage affected males have abnormalities of the nipples including absent, simple or accessory nipples feeding problems in infancy xerostomia,hoarse voice & impacted cerumen

42. Craniofacial features: Distinctive facies with frontal bossing, concave midface , saddle nose and everted lips 30% of affected males have small ears facial features may not be obvious at birth, but become more noticeable with age

43. HistoPathology : The epidermis is thin with effacement of rete ridges. Hair follicles and sebaceous glands, Apocrine glands are variably reduced Mucous glands of the upper respiratory tract may be sparse

44. Light and scanning electron microscope findings of hair shaft abnormalities are longitudinal clefts or grooves and transverse fissuring,bulb of the hair shaft is dystrophic Mandible X-ray show Dental hypoplasia or aplasia

45. Epidermal & follicular orthokeratotic hyperkeratosis Arrector Pili muscle oriented parallel to skin surface Apocrine ducts enter follicles at abnormal locations Comedo formation

46. Prognosis: Failure to thrive occurs in up to 40% of affected males Height and weight are compromised in early childhood but appear to normalize with time. Mortality in infancy and early childhood is historically 25% Due to hyper thermia , failure to thrive and respiratory infections

47. Diagnosis Associated Hyperthermia desreves in early diagnosis in childhood Careful clinical examination Standard methods for Sweat production & Sweat pore counts by Silicone rubber plastic imprints,Starch – Iodine test,Pilocarpine iontophoresis,Valerio Ventruto Tech ( Palmar finger tip Sweat pore counting )

48. Skin biopsy : absence or sparse sweat glands in dermis of hypothenar area decrease no of sebaceous glands & hair follicles in other areas

49. Mortality/Morbidity: related to the absence or dysfunction of eccrine and mucous glands. Intermittent hyperpyrexia may occur in infants with decreased sweating. The mortality rate approaches 30%. Recurrent high fever may also lead to seizures and neurological sequelae

50. Pharyngitis , rhinitis, cheilitis dysphagia may result from reduced numbers of functional mucous glands in the respiratory and gastrointestinal tracts. Growth failure is common.

51. What is the treatment for ectodermal dysplasia? No specific treatment for ectodermal dysplasia Management of ED is by treating the various symptoms Patients often need to be treated by a team of doctors and dentists, rather than a sole practitioner abnormal or no sweat gland function should live in cooler climates or in places with air conditioning at home, school and work.

52. Artificial tears can be used to prevent damage to the cornea in patients with defective tear production Saline irrigation of the nasal mucosa may help to remove purulent debris and prevent infection Early dental evaluation and intervention is essential

53. Surgical procedures such as repairing a cleft palate may lessen facial deformities and improve speech. Research on Gene correction or administration of recombinant EDA protein. Proof of principle has been achieved in a dog model for this approach

54. Psychological support for affected children Prevention : Prenatal Diagnosis by fetal skin biopsy possible after 24 weeks of gestation ( Sweat gland start to develop ) Glands may be shriveled or absent DNA probing tech on Chorionic Villus Biopsy

55. Differential Diagnosis infants with scaling skin may be misdiagnosed as collodion babies with lamellar ichthyosis Basan syndrome is characterized by hypotrichosis , hypodontia and hypohidrosis , but also by severe nail dystrophy and congenital absence of dermatoglyphics

56. Differential Diagnosis: Alopecia Areata Aplasia Cutis Congenita Focal Dermal Hypoplasia Syndrome Incontinentia Pigmenti Naegeli - Franceschetti-Jadassohn Syndrome Pachyonychia Congenita

57. Hidrotic Ectodermal Dysplasia ( Cloustons Syndrome ) Palmoplantar keratoderma Hypotrichosis Nail dystrophy Genetics : AD pattern,ED 2, Ch 13q11-q12.1,member of Gap jn family connexin - 30

58. Clinical features : Nail dystrophy – MC,short discolored, thickened with striations are seen over bulbous finger tips

59. Scalp hair: thin,brittle,normal at birth gradually hair loss & total alopecia Axillary & Pubic hair are vellus or sparse or absent Diffuse palmoplantar keratoderma with deep fissuring Sweating is normal

60. Skin thickening beneath free edges of nails,finger joints,knuckles Thickening of skull bones,tufting of terminal phalanges of fingers and nails Oral leukoplakia may be seen Teeth may be normal,prone to Early Caries

61. Syndactylyl & Polydactylyl Mental & Physical Retardation

62. Diagnosis : Palmoplantar Keratoderma normal facies , normal sweating & teeth differentiate . Prognosis: Life expectancy will be normal Persistent Malodourous Onychomycosis Squamous cell carcinoma of nail bed

63. Management: Keratolytic agents & Emollients for PPK Systemic Retinoids

64. Ectrodactylyl-Ectodermal Dysplasia-Cleft Lip ( EEC Syndrome) Very Rare, Both Mesodermal & Ectodermal structures Described by COCKAYNE in 1936 3 types: EEC 1, EEC 2, EEC 3

65. GENETICS : AD pattern Mutation of P 63 gene ( similar to P53) located on Ch 7q11.2-q21.3 P63 is critical to maintain Progenitor cells responsible for Genesis of Limbs & Cranio facial regions in fetal life

66. Clinical features: Lobster claw deformity: Split hand & foot – MC 3 rd & 4 th Digits - MC Tetramelic involvement –MC Nails Hypoplastic & Dystrophic Cleft Palate & Lip

67. Typical face : Hypoplastic Maxillae, Short Philtrum , Broad Nasal tip Oligodontia & Anodontia Hair: Sparse,dry,scalp dermatitis MR, hamartoma of tongue, hydronephrosis

68. Diagnosis Major Minor ED Ectodactyly Cleft Palate/Lip Lacrimal duct abnor . Renal Anomolies Deafness MR Choanal atresis X – Ray of deformed hand show absence or hypoplasia of Meta carpals & Metatarsals

69. Prognosis : Corneal Scarring & Blindness due to Recurrent Keratitis Treatment : Repair of Cleft palate & Lip Multi disciplinary approach for other abnormalities Prevention : Cleft Lip/Palate – Prenatally by USG

70. Rapp-Hodgkin Syndrome/Hay-Wells Syndrome ( AEC Syndrome ) Genetics : AD Pattern Missense Mutation in SAM domain of P 63

71. cleft lip/palate hypotrichosis , hypodontia , absent or dystrophic nails ,mild hypohidrosis One distinctive feature is ankylo blepharon filiforme adnatum —partial thickness fusion of the eyelid margins

72. severe scalp erosions Scalp dermatitis with erosions may result in scarring alopecia

73. CLINICAL FEATURES : Babies at birth have Erythroderma – MC Peeling, red, parchment-like skin in a newborn parchment skin resolves over the first few weeks of life and the underlying skin is dry

74. Marked hypohidrosis – heat intolerance Hair is sparse, pale with STEEL WOOL Texture Hair shaft abnormalities – PILI TORTI Nail dystrophy, Cleft palate /Lip

75. Abnormal hair shaft showing PILI TORTI & Longitudinal groove ( PILI CANALICULI )

76. Hands of son and father showing brittle,thin & dystrophic nails

77. Face : Frontal bossing ,maxillary hyperplasia narrow nose, broad nasal bridge & small mouth Fusion of EYE LIDS most distinc feature Hypodontia or Conical Teeth

78. VSD Syndactylyl , Treatement : Surgical correction of eye lids Correction of Hyperhidrosis

79. Johanson -Blizzard Syndrome AR inheritance Cong. Membranous aplasia cutis of scalp Deafness,Dwarfism MR,Hypotonia Genital abnormalities DM,Hypothyroidism

80. Schopf -Schultz- Passarge Syndrome AR inheritance Cysts at eyelid margins Palmo plantar keratoderma Hypotrichosis Hypodontia Benign & Malignant tumors of Palms & Soles

81. Syndromes with ectodermal dysplasia • Berlin syndrome : Generalized grayish -brown hyperpigmentation with Sparse eyebrows with absent lateral aspect, delayed dentition/ hypodontia , short stature, sexual underdevelopment in male patients, mental retardation Described in one family (Iranians living in Israel; four affected siblings; consanguineous parents)  

82. Lucky/Winter syndrome Generalized hyperpigmentation with guttate Scant lightly pigmented hair, enamel hypoplasia (single central incisor in one patient), Likely autosomal dominant inheritance 

83. Acromelanosis albo-punctata syndrome Diffuse hyperpigmentation with atrophic skin guttate on the dorsal aspects of the hands and feet Keratotic follicular papules on the legs pili torti platonychia

84. Nails Hair Teeth Sweat gland others HYPO HIDROTIC ED Gen Normal Dry,hypochromic & hypotrichosis of scalp Moustache & Beard - Normal Eye brow & Lashes - absent Hypodontia Peg shaped incisors / canines Dec Epidermal ridge sweat pores Skin – thin,dry - abs sebaceous gl Face : Saddle nose ,frontal bossing Pharyngitis Laryngitis Aplasia of Breast HIDROTIC ED Thickened/ discoloured , clubbing Dry,Slow Growing, Eye brow/ Lashes- Scanty or abs Occ Anodontia / hypodontia , caries Normal Skin- Dry,scaly Thick dyskeratotic palms & soles Tufting of terminal Phalanges ,myopia EEC ED Thin, pitted, striated nails Hypotrichosis of scalp,body Eye brow/Lashes - abs Ano /hypo/micro dontia Occasionally hypohidrosis without hyperthermia Palmoplantar hyperkeratosis ,cleft lip/ palat,speckled iris,syndactylyl,ectrodatylyl,clinodactylyl , AEC Sever dystrophy Hypotrichosis Steel wool texture PILI TORTI PILI CANALICULI Sever hypodontia Hypohidrosis but no hyperthermia Dry smooth,pp hyperkeratosis, dermatoglyphic patter- abs, Scalp pustulation

85. No / Severely reduced sweating Sev Immune defect HED/IM No Immune eff. X-LR HED AD- HED AR-HED Normal/mild dec sweating Normal teeth Clouston ED/skin fragility Abnormal teeth No facial cleft Tooth & nail / witkop Trichodentoosseous Facial cleft Limb abnormality + EEC Margarita island ED Limb-mammary Limb abnormality – AEC Rapp- Hodgkin ED

86. One well known person with ED is Actor Michael Berrymen

87. Famous Skate boarder & artist Levi Hawken,well known with Nek Minit Videos on you tube

88. Thank You Very Much

89. Thank you