INHERITED CONNECTIVE TISSUE DISORDERS

Ehlers-Danlos syndrome (EDS)

(Cutis hyperelastica)
• abnormal collagen structure and/or function in skin, joints, vasculature
• Classical EDS (most common subtype)
Collagen 5
■ May deliver/be delivered pre-term as a result of early rupture of fetal
membranes; normal life span
■ Mucocutaneous manifestations
○ Velvety, soft, and doughy consistency of skin
○ Marked hyperextensibility of skin
○ Poor wound healing (“cigarette paper” scars)
○ Widened atrophic cutaneous scars (“fishmouth” wounds)
○ Piezogenic pedal papules
○ Fragile blood vessels → hematomas and easy bruising
○ Subcutaneous spheroids (fat lobules that have calcified after losing their
blood supply)
○ Molluscoid pseudotumors associated with scars over knees and elbows
○ Blue sclerae
○ Gorlin’s sign: ability to touch tip of nose with tongue (50%)
■ Musculoskeletal manifestations
○ Generalized joint hypermobility
○ Double-jointed fingers
○ Frequent subluxation of larger joints
○ Chronic joint and limb pain
○ Kyphoscoliosis
○ Pes planus
■ GI manifestations
○ Hiatal/inguinal hernia,
postoperative hernias, and anal prolapse
○ GI bleeding/rupture
■ Cardiac manifestations
○ Mitral valve prolapse
○ Aortic root dilation
 Ehlers-Danlos Syndrome type with
congenital adrenal hyperplasia is
caused by mutations in tenascin-X.
Tenascin X
• Hypermobile EDS
■ Not prone to life-threatening complications
■ Severe joint laxity, recurrent dislocations/ subluxations, and chronic
joint pain +/− arthritis
■ Mitral valve prolapse
■ Symptoms of autonomic dysfunction, including postural orthostatic
tachycardia syndrome (POTS)
■ GI and urinary symptoms
Collagen 3
• Vascular EDS
■ Life-threatening risk of blood vessel and organ rupture → sudden death
in third/fourth decade (arterial or colonic rupture; maternal death may
occur as a result of uterine or arterial rupture)
■ Cutaneous manifestations
○ Easy bruising
○ Thin and translucent skin with visible underlying blood vessels
○ Skin is not hyperextensible, but can be fragile
○ Lack of subcutaneous fat
■ Facial features: thin, pinched nose; prominent sunken eyes; thin upper
lip; and lobeless ears
■ Blue sclera (>90%)
■ Acrogeria
■ Hypermobility limited to digits
■ Congenital talipes (club foot)
■ Recurrent pneumothoraces
■ Arterial (including aorta) dissection, rupture, and aneurysm of medium-
sized vessels
○ Spontaneous rupture of arteries (medium-sized) may occur during
childhood, and incidence peaks during third and fourth decade
○ Intestinal rupture is common (sigmoid colon #1 site)
■ Intracranial aneurysms associated with cerebrovascular accidents
■ Obstetric complications, including uterine and arterial rupture, massive
postpartum hemorrhage, and severe laceration from tearing at vaginal
delivery
■ Short stature XLR EDS
Lysyl oxidase deficiency /type V
occipital exostoses and hernias/ Type IX
AR EDS
kyphoscoliotic/type IV
dermatosparaxis/ type VII C
Type Genes Skin Findings Joint Changes Other
Hyperextensibility
Easy bruising
Fragile skin
Widened atrophic (“fish
mouth” or “cigarette
paper”) scars
Classical Molluscoid
(formerly pseudotumors(overlying
Type I, “gravis” extensor joints and Hypermobility (+)Gorlin’s sign
and Type II, COL5A1, pressure points) and joint Absence of lingual
“mitis”) COL5A2 AD Spheroids dislocations frenulum
Similar to mild classic type
Classic-like EDS TNXB AR but normal scarring tenascin-X
Cardiac valvular Cardiac valve defects,
otherwise similar to the α2-chain of type I
COL1A2 AR classic type collagen
Hypermobility
Chronic joint variable autonomic
pain + arthritis dysfunction
Hypermobility TNXB Recurrent Mutations in tenascin-
(formerly Type tenascin AD dislocations / X result in EDS with
III) X /AR Mild subluxations CAH
Thin, translucent skin Mnemonic: “IV =
Extensive bruising blood vessels”
Early varicosities Rupture of bowel,
Vascular (can visualize veins under uterus, or arteries
(formerly Type skin easily) Small joint Most life-
IV) COL3A1 AD Acrogeria hypermobility threatening form
Severe muscle
hypotonia
Ruptured globe,
blindness, retinal
detachment, or
keratoconus
Marfanoid
Lysyl Osteopenia
Kyphoscoliotic hydroxyl Ascorbic acid
(formerly Type ase 1 Hypermobility supplementation may
VI A) (PLOD1) AR Mild Severe scoliosis help
CHST14/
dermata joint
n-4- Hyperextensible and fragile contractures ocular fragility,
Musculocontract sulfotran skin, wrinkled palms, hypermobility, craniofacial
ural VIB sferase 1 AR scoliosis abnormalities
Type Genes Skin Findings Joint Changes Other
Most severe
hypermobility
with recurrent
subluxations/
dislocations
(much more
Arthrochalasic severe than Congenital hip
(formerly Types COL1A1, Hypermobility dislocation
VIIa and VIIb) COL1A2 AD Mild type) Short stature
Procollag
en N-
proteina Umbilical/inguinal
Dermatosparaxis se Severe fragility hernias
(formerly Type (ADAMT Sagging, redundant skin, Premature rupture of
VIIc) S2) AR and bruising Mild fetal membranes
Periodontitis
type complem Hyperextensible skin with Severe
(formerly Type ent scarring (esp. pretibial) and periodontitis →teeth
VIII) C1r, C1s AD bruising Mild loss
variable joint
hypermobility,
hypotonia,
Spondylodysplas limb bowing,
tic short stature,
(includes former variable tapered
progeroid and B4GALT6 fingers,
spondylocheirod /7: Soft/doughy, translucent, osteopenia,
ysplasia SLC39A1 and/or hyperextensible developmental
types) 3: AR skin, delay
ocular fragility,
Soft, translucent skin with keratoconus, blue
Brittle cornea ZNF469 variable hyperextensibility hypermobility of sclerae, impaired
syndrome PRDM5 AR and fragility, acral wrinkling small joints, hearing, scoliosis
COL12A1
/α1- proximal joint
chain of contractures Congenital myopathy
type XII AD Soft/doughy skin with and distal with hypotonia that
Myopathic collagen /AR atrophic scarring, hypermobility improves with age
The historical EDS types
types V (X-linked) and X (fibronectin)
EDS types IX and XI have been reclassified as occipital horn syndrome and familial joint hypermobility
syndrome, respectively.
heterozygous mutation in the elastin microfibril interfacer 1 (EMILIN1) gene was identified in a
patient with increased skin elasticity, aortic aneurysms, sensorimotor peripheral neuropathy, and
arthropathy
Periodontitis in Geno
1-papillon lefevre/Haim Munk syndromes
2-PPK with sex reversal
3-EDS type 8
Benign hypermobile type
EDS
Gronblad-Strandberg syndrome =
Pseudoxanthoma elasticum

• AR disorder as a result of mutations in ABCC6 (ATPbinding cassette,

subfamily C, member 6) gene → 2° mineralization of the elastic tissue of
the eyes, skin, and arteries
• Presents during childhood or 2nd/3rd decade of life
1- Cutaneous manifestations
■ Thin, yellowish papules in flexural areas arise during first or second
decade of life
○ Typically first appear on the lateral aspects of the neck
○ Papules coalesce to form cobblestone-like plaques resembling “plucked
chicken skin”
○ Antecubital and popliteal fossae, wrists, axillae, groin, and periumbilical
area (in multiparous women) are involved
○ Perforating PXE: in advanced disease, ↑dermal calcium deposition and
extrusion of this yellowish material through the epidermis may occur
○ Loss of recoil and sagging skin in axillae and groin
○ Yellow papules may develop in oral/anogenital mucosa
2- Ocular manifestations
■ Asymptomatic angioid streaks (Bruch’s membrane rupture) usually in
first decade
○ “Owl’s eyes”: paired areas of hyperpigmented spots straddling an
angioid streak
○ Agioid streaks also seen in Paget’s disease of bone, sickle cell anemia,
thalassemia, EDS, lead poisoning, and age-related degeneration
■ Macular degeneration, optic drusen, and retinal hemorrhage (→
blindness)
■ Mottling of retinal pigment epithelium
○ Most prevalent ophthalmologic finding; may precede development of
angioid streaks
3- Cardiovascular manifestations
■ Intermittent claudication, loss of peripheral pulses, renovascular
hypertension, mitral valve prolapse, angina/myocardial infarction, and
stroke
■ Progressive calcification of elastic media and intima
→ atheromatous plaques involving predominantly
medium-sized arteries (esp. in extremities)
4- GI manifestations
■ Gastric artery hemorrhage, hematemesis, epistaxis
• Obstetric complications
■ ↑risk of first trimester miscarriage and maternal
cardiovascular complications
• On histology, distorted, basophilic, and fragmented calcified elastic
fibers in mid/deep reticular dermis
• Morbidity and mortality 2° to GI hemorrhage, cerebral hemorrhage,
atherosclerotic disease, and myocardial infarction
 *A diet high in magnesium was shown to reduce
connective tissue mineralization in a mouse model
of PXE50; clinical trials are in progress.
Studies in mice have shown reduced dystrophic
calcification with administration of
bisphosphonates or 4-phenylbutyrate, which
promotes maturation of mutant ABCC644,45;
clinical trials are in progress. VEGF, vascular
endothelial growth factor.
 ATP7A
Cutis laxa/generalized elastolysis 1-Menkes disease
2-XLR cutis laxa (occipital horn syndrome,
previously EDS IX)
ATP7B
Wilson’s disease

• AD forms (less common): elastin gene (ELN) or fibulin 5 (FBLN5)

mutations → dysregulation of elastic fiber network in the skin mainly
(internal involvement uncommon); presents in early adulthood
• AR forms (most common): FBLN5, EFEMP2/FBLN4, LTBP4, ATPase,
ATP6V0A2, PYCR1, and ALDH18A1; presents at birth to early childhood; skin
+ severe internal involvement
• XLR form (occipital horn syndrome, previously EDS IX): mutations in
ATP7A (allelic to Menkes disease)

• “Aged” facial appearance (hound-dog facies) with down-slanting

palpebral fissures and a long philtrum
• Loose, sagging skin with reduced elasticity and resilience; deep voice 2°
to vocal cord laxity
• Histology: sparse and/or fragmented elastic fibers
• AD cutis laxa
■ Primarily generalized cutaneous findings, cardiac valve abnormalities,
aortic dilatation (variable), emphysema (uncommon), and hernias
• AR cutis laxa (ARCL)
■ ARCL type I
○ FBLN5, EFEMP2, or LTBP4 mutations
○ Potentially fatal involvement of lungs (hypoplastic lungs and
emphysema)
○ Cardiovascular abnormalities (aortic tortuosity and aneurysms)
○ Inguinal/diaphragmatic/umbilical hernias
○ GI/genitourinary diverticula
○ Joint laxity, arachnodactyly, and fractures (variable)
■ ARCL type II
○ ATP6V0A2 (type IIA) or PYRC1 (type IIB) mutations
○ Craniofacial anomalies
○ Delayed growth and development
○ Cutaneous features may be primarily acral
○ Pachygyria (IIA) and absent corpus callosum (IIB)
○ Translucent skin (IIB)
○ Joint laxity
○ Strabismus/myopia
○ Improves with age
■ ARCL type III (De Barsy syndrome)
○ ALDH18A1 (type IIIA) or PYRC1 (type IIIB) mutations
○ Developmental delay/dystonia/neurologic deterioration
○ Progeroid appearance
○ Reduced subcutaneous fat
○ Athetosis
○ Hyperammonemia (in some patients)
○ Corneal clouding/cataracts
• XLR cutis laxa (now termed Occipital Horn Syndrome)
■ Easy bruising and coarse hair (variable)
■ Tortuous arteries
■ Genitourinary diverticula
■ Inguinal, diaphragmatic and umbilical hernias
■ Long face w/ high forehead and hooked nose
■ Wedge-shaped occipital calcifications (occipital horns)
■ Hip dislocations (joint laxity)
• Acquired cutis laxa
■ Primarily adults w/ sagging of skin and little associated internal
involvement
■ Cutaneous involvement may be primarily acral; generalized involvement
typically begins on the face/ neck
■ May occur in association with drugs (penicillamine and isoniazid), other
cutaneous disorders (e.g., cutaneous lymphoma, Sweet syndrome-like
eruption, interstitial granulomatous dermatitis, and cutaneous
mastocytosis) or systemic disease (rheumatoid arthritis, sarcoidosis, SLE,
and infectious disorders)
Osteogenesis imperfecta (OI)
• Mutations in type I collagen → fragile bones (poor cortical modeling and
less trabecular bone formation)
• There are at least 8 well-defined types, but Types I–IV account for 90%
■ Types I (most common form, accounts for 50% of OI; generally mild;
fractures in childhood and adolescence). Mitral valve prolapse is seen
especially in Type I.
II (most severe form, fatal in perinatal period),
III (progressive and deforming), and IV
○ AD inheritance; due to mutations in type I collagen genes COL1A1 and
COL1A2
■ Onset (birth to adulthood) and severity depend on type
• Cutaneous manifestations
■ Thin, atrophic, and translucent skin
■ Easy bruisability
■ Scars may be atrophic or hypertrophic
• Musculoskeletal manifestations
■ Hyperlaxity of ligaments and hypermobility of joints
■ Brittle bones + fractures (skull, long bones, and vertebrae;
occurs in utero in severe forms)
■ Scoliosis
■ Beaded ribs
■ Limb deformities
• Other manifestations
■ Blue sclerae are seen ~90% of patients
■ Otosclerosis with hearing loss may begin during adolescence
■ Fragile/discolored teeth
■ Dentinogenesis imperfecta (DI)
■ Mitral and aortic valve prolapse/dilatation and regurgitation
■ Cystic medionecrosis of the aorta
■ Neurologic features include macrocephaly, hydrocephalus, syringomyelia,
and basilar invagination
• Variable prognosis depending on disease type and severity:
■ Types I and IV: normal life span
■ Type II: death in perinatal period
■ Type III: increased mortality in 3rd/4th decade due to respiratory failure
(secondary to kyphoscoliosis) or head trauma
 Marfan is tall= looking up

Marfan syndrome (MFS)

• AD mutations in the FBN1 gene (encodes fibrillin-1)
• Manifestations may not present until adolescence or in 30s–40s
• Tall with long extremities (marfanoid habitus)
■ Arm span is characteristically greater than height
■ After puberty, upper segment (vertex to pubis) to lower segment (pubis
to sole) ratio is <0.86
• Lack of subcutaneous fat, presence of striae on upper chest, arms, thighs,
and abdomen and increased risk of elastosis perforans serpiginosa
• Skeletal manifestations
■ Arachnodactyly
■ Kyphoscoliosis, pectus excavatum, and dolichocephaly
■ Pes planus
■ Joint laxity, patellar dislocation, and hip dislocation
• Ocular manifestations
■ Ectopia lentis (upward lens displacement
60% of patients)
■ Ocular globe elongation leading to myopia (~40%)
■ Retinal detachment, cataracts, and glaucoma
• Cardiovascular manifestations (70%)
■ Dilatation of ascending aorta → regurgitation, CHF, dissection/
aneurysm, and rupture
■ Mitral valve prolapse
■ Left ventricular dilation
■ Cardiac complications may → death
• Pulmonary manifestations
■ Spontaneous pneumothorax, apical blebs, and bullous emphysema
 Crumpled ears are characteristic

The most common associated disorder in a patient with

elastosis perforans serpiginosa is: Marfan syndrome. About 1/3
of case of elastosis perforans serpiginosa occur in patients with
other concomitant disorders

Tip malar flush+ DVT... Think of

1-SLE 2-homocystienuria
Buschke-Ollendorf syndrome
• AD disorder due to mutation in LEMD3/MAN1 (LEM domain-containing-
3/MAN antigen 1) gene → ↑TGF-β signaling
• Dermatofibrosis lenticularis disseminata (collagen-type nevus, also called
juvenile elastomas) on buttocks, proximal trunk, and limbs
■ Symmetric, small, uniform, yellow to skin-colored dermal papules
coalescing into plaques; onset in childhood (typically in 1st year of life)
• Osteopoikilosis (“spotted bones”)
■ Asymptomatic circular densities in carpal bones, tarsal bones, phalanges
of hands and feet, pelvis, and epiphyses and metaphyses of long bones
■ Often noted incidentally on plain films (1- to 10-mm round opacities)
• Histology: abundant thickened collagen fibers and elastic fibers (often
fragmented and clustered into nets)
Lipoid proteinosis (hyalinosis cutis et mucosae, Urbach-Wiethe disease)
• AR disorder due to mutations in the extracellular matrix protein 1
(ECM1) gene; ↑ in South Africa
• Thickening of basement membrane and deposition of hyaline material in
dermis → characteristic thickening of the skin, mucous membranes, and
certain viscera
• Hoarse cry or weak cry from infiltrated vocal cords is the first clinical sign
(occurs in infancy and persists for life)
• Cutaneous lesions develop during first few 2 years of life in two
overlapping stages
■ First stage: vesicles and hemorrhagic crusts involving the face,
extremities, and oral mucosa develop in association with trauma and
resolve with “ice-pick” scars
■ Second stage: ↑hyaline deposition within the dermis → yellow, waxy,
and coalescing papules/nodules on the face/neck and extremities; beaded
eyelid papules resembling “string of pearls” (50%)
Verrucous nodules on elbows/knees/hands
• Infiltration by yellow papules/plaques of mucosa of pharynx, soft palate,
tonsils, and lips
• Thickened “woody” tongue; inability to protrude tongue (due to
shortened frenulum)
• Respiratory difficulty a/w upper respiratory tract infections and may
require tracheostomy; occasionally fatal in infancy (major cause of early
death)
• Neurologic manifestations include seizures and neuropsychiatric
symptoms, a/w pathognomonic sickle or “bean-shaped” calcifcations in
temporal lobes or hippocampus
• Histology: deposition of amorphous or laminated basement membrane-
like material containing collagen (types II and IV) and laminin around
blood vessels, dermal-epidermal junction, adnexal epithelia, and in
connective tissues (appears as vertically oriented pink dermal deposits)
■ Deposits are PAS(+) and diastase-resistant
Focal dermal hypoplasia (Goltz syndrome, Goltz-Gorlin syndrome)
FOCAL has been suggested as an acronym that
incorporates the key clinical features of this disorder:
■ Female, XLD, Fat herniation
■ Osteopathia striata
■ Colobomas
■ Aplasia of ectodermal elements
■ Lobster claw deformity

• X-linked dominant (XLD) disorder due to mutations in the PORCN

(porcupine) gene (regulator of Wnt signaling proteins, which are critical for
embryonic development of skin, bone, teeth, and other structures)
• Majority of patients are heterozygous females (90%);
lethal in males
• Cutaneous manifestations:
■ Widely distributed linear/Blaschkoid areas of hypoplasia/atrophy of the
skin, with telangiectasias
■ Soft, yellow to reddish-yellow nodular outpouchings caused by
herniation of subcutaneous fat through thinned dermis
■ Dysmorphic facies (notched nasal ala and malformed ears)
■ Large cutaneous ulcers (from a congenital absence of skin) that heal w/
atrophic scarring
■ Streaky hyper- and/or hypopigmentation
■ Red (“raspberry-like”) papillomas; favors lips, anogenital region, larynx
and acral skin
■ Hair is thin or absent
■ Dystrophic or completely absent nails
• Skeletal manifestations
■ Oligodactyly, syndactyly, ectrodactyly (lobster claw deformity), and
polydactyly
■ Microcrania, asymmetric development of skull, pointed mandible, and
deviated nasal septum
■ Scoliosis, kyphosis, spina bifida occulta, rudimentary tail, and fusion of
vertebral bodies
■ Osteopathia striata: vertical striations in long bone metaphyses on X-ray
• Ophthalmologic manifestations (40%)
■ Colobomas of iris/choroid/retina/optic disc
■ Strabismus
■ Anophthalmia, microphthalmia, and incomplete development of the
retina and optic nerve
■ Hypopigmented/hyperpigmented retina, cloudy vitreous, and subluxation
of lens
• Dental manifestations
■ Underdeveloped, dysplastic, or absent teeth
■ Delayed eruption of primary dentition
■ Notched incisors
■ Enamel hypoplasia
■ Severe malocclusion if mandible is malformed
• Intelligence usually normal, though severe mental impairment has been
reported
• Histology: markedly decreased/absent dermis with herniated fat located
abnormally close to epidermis

Vertical striations around the knee in osteopathia striata

• Allelic autosomal recessive (AR) diseases caused by mutations in ANTXR2/
CMG2 gene (capillarymorphogenesis protein-2) → abundance of hyalinized
fibrous tissue in skin and internal organs
■ ISH presents within first 6 months of life with cutaneous, mucosal,
skeletal, and internal organ involvement and death in early childhood
■ JHF presents during early childhood with cutaneous, mucosal, and
skeletal/joint (often debilitating) involvement only; survival into adulthood
• Cutaneous manifestations
■ Thickened skin and hyperpigmentation overlying bony prominences is
characteristic of ISH
■ Perianal nodules
■ Small pearly papules on ears and face (perinasal and perioral)
■ Scalp nodules are characteristic of JHF
• Oral manifestations
■ Thickening of oral mucosa
■ Gingival hypertrophy
■ Marked curvature of dental roots
■ Replacement of periodontal ligament by hyaline fibrous material
■ Feeding difficulty
• Musculoskeletal manifestations
■ Debilitating joint contractures and tumors
■ Osteolytic bone lesions are characteristic of JHF
• Normal intelligence
• Visceral involvement (ISH only): hyaline deposits develop in multiple
internal organs w/ recurrent infections, malabsorption, protein-losing
enteropathy, and failure to thrive
• Histology: ↑# of fibroblasts embedded in hyalinized connective tissue
stroma that is homogeneous, amorphous, and acidophilic (PAS-positive)
• ISH has a poor prognosis with death by 2 years of age from recurrent
pulmonary infection and GI complications
• In JHF, survival into adulthood (death often by 4th decade)