Connective tissue

Question 1

Progeria
AKA
Inheritance
Age at presentation

Answer 1

Hutchinson-gilford syndrome
AD, lamin A gene
Presents 1st to 2nd year of life

Question 2

Progeria
Pathogenesis
DDx
Ix
Prognosis

Answer 2

Mutation in lamin A, a nuclear envelope protein
DDx: cockayne, werner, hallerman-streiff
Urinary hyaluronic acid increased
Premature death due to atherosclerosis in 2nd decade

Question 3

Progeria

Key features

Answer 3

Skin:Thin, atrophic, prominent scalp and thigh veins, loss of sc fat, mottled hyperpigmentation, sclerodermoid changes on lower trunk and thigh
Hair: spare to absent scalp hair, eyebrows, eyelashes, downy, fine hair may persist
Nails: thin, dystrophic
Craniofacial: large cranium, frontal and parietal bossing
MSK: failure to thrive, 2nd year of life, OP, wasting
CVS: severe atherosclerosis with angina, MI, CVA
Mouth: abnormal and delayed eruption of permanent teeth, high pitches, squeaky voice
Psychosocial: severe problems related to appearance

Question 4

Werner syndrome 
Inheritance
Age at presentation
Pathogenesis
DDx
Lab data
Prognosis

Answer 4

AR, RECQL2 gene or WRN gene
Presents 3rd-4th decade
Mutation in RECQL2, a DNA helicase enzyme, increased frequency of recombination with a predisposition toward accelerated aging and cancer
DDx: progeria, rothmund Thomson, scleroderma, myotonic dystrophy
Lab data: urinary hyaluronic acid increased; fasting serum glucose, xray of extremities
Prognosis: premature death from malignancy, MI or CVA: 4th-6th decade

Question 5

Werner syndrome

Features

Answer 5

Skin: sclerodermoid features, atrophy, mottle hyperpigmentation, telangiectasias, soft tissue calcification, leg ulcers, circumscribed hyperkeratoes
Hair: canities, progressive premature hair loss
MSK: short stature, with growth arrest at puberty, muscular wasting
Eyes: posterior, subcapsular cataracts
ENT: high pitched, hoarse voice
CV: premature atherosclerosis with angina, myocardial infarction
Endocrine: DM, hypogonadism
Neoplasm 10% : fibrosarcoma, osteosarcoma, cutaneous cA, meningioma, adenoca

Question 6

Lipoid proteinosis 
Inheritance
Age at presentation
DDx
Lab data
Prognosis

Answer 6

Inheritance: AR, extracellular matrix protein 1 (ECM1) gene
Age at presentation (hoarse cry) at birth to 1st few years of life.
DDx: amyloidosis, EPP, pseudoxanthoma elasticum, xanthomas
Lab data: skin bx (PAS + hyaline material), MRI
Prognosis: may involve internal organs, but chronic & benign course with normal life span; laryngeal involvement may lead to resp difficulties

Question 7

Lipoid proteinosis

Clinical features

Answer 7

Skin
- Early: bullae with residual atrophic scarring on face, neck and extremities
- Late: yellow papules, nodules on face, neck, extremities with eyelid string of pearls. Verrucous nodules of elbows, knees and hands
Hair: patchy alopecia in scalp, beard, eyelashes
Mucous membranes: yellow papules & plauqes on pharynx, lips, soft palate, with/without parotitis caused by stenotic parotid duct
ENT: hoarse cry due to vocal cord infiltration, large, wooden tongue
CNS: temporal and hippocampal calcification

Question 8

Aplasia cutis congenita
Inheritance
Age at presentation
DDx

Answer 8

Inheritance: AD or AR or sporadic
Age at presentation: birth
Pathogenesis: depends on subtype; genetic defect, trauma, teratogen, infection – absence of epidermis, dermis or SC with/without underlying bone (20-30%)
DDx: Trauma from scalp monitor, forceps, naevus sebaceous, localised scalp infection, congenital dermoid cyst, scarring alopecia, meingocele, heterotopic neural tissue, HSV

Question 9

ACC
Lab data
Prognosis

Answer 9

Lab data: viral/bacterial mcs, skin bx if diagnosis uncertain but cranial USS first
Prognosis: most heal within weeks to months, leaving a hairless, smooth, yellowish atrophic scar.

Question 10

Aplasia cutis
General features
Groups

Answer 10

0.5-10cm solitary (70%), or multiple well demarcated superficial erosions, deep ulceration with thin membrane or atrophic scars with alopecia on scalp (80%); heal with scar within weeks after birth. Larger lesions, possible extension to dura mater
Group1: AD or sporadic: scalp ACC without multiple anomalies
Group2: scalp (midline) with limb abnormalities eg hypoplastic or absent phalanges, hands, lower extremities, cutis marmorata (Adams Oliver)
Group3 (sporadic): scalp with associated epidermal or organoid naevi; organoid naevi, melanocytic naevis, epidermal naevi, corneal opacities, mental retardation, seizures
Group4: overlying embryologic malformations: meningomyeloceles, spinal dysgraphia, omphaloceoele, gastrochisis.
Group5: (sporadic) associated foetus papyraceus or placental infarcts
Group6: EB
Group7: localised to extremities without blistering
Group 8: teragens or intrauterine infection – may be associated with varicella/HSV
Group 9: Malformation syndromes eg trisomy 13, 4p syndrome, ectodermal dysplasias, focal dermal hypoplasia, amniotic band syndrome, Opitz syndrome, Adams-Oliver, oculocerebrocutaneous syndrome

Question 11

Aplasia cutis

Some isolated defects which may occur with group 1

Answer 11

Isolated abnormalities (most often associated with membranous ACC): cleft lip and/or palate, tracheoesophageal fistula, high myopia and cone-rod dysfunction, patent ductus arteriosus, intestinal lymphangiectasia, omphalocele, polycystic kidneys, double cervix and uterus, mental retardation, temporal triangular alopecia

Question 12

Which syndrome is group 2 aplasia cutis associated with?

Answer 12

Group 2: Adams-Oliver

Question 13

Complications of aplasia cutis

Answer 13

Complications: deep ACC of the scalp include life-threatening sagittal sinus hemorrhage/thrombosis and meningitis

Question 14

Focal dermal hypoplasia
Synonym
Inheritance
Age at presentation

Answer 14

Goltz syndrome
X linked dominant
Birth

Question 15

Goltz syndrome
DDx
Lab data
Prognosis

Answer 15

DDx: IP, naevus lipomatous superficialis, Rothmund-thomson
Lab data: skin bx, xray long bones
Prognosis: skeletal deformities, cosmetic deformities, ocular.

Question 16

Focal dermal hypoplasia

Features

Answer 16

Skin : asymmetric atrophic, hyperpigmented, or hypopigmented, soft red-yellow nodules (fat herniations) in blaschko’s lines. Ulcers at sites of congenital absence of skin that heal with atrophy (15%), papillomas on the lips, perineum, axilla, periumbilical area.
Hair: sparse, brittle; patchy alopecia in scalp or pubic area
Nails: absent or dystrophic on fingers and toes
Eyes: coloboma, strabismus, microphthalmia
MSK: syndactylyl, lobster claw, osteopathia striata (vertical striations in metaphysis of long bones on xray ) – 80%
Mouth : hypodontia, oligodontia; small teeth
Craniofacial: small, rounded, asymmetric face; notched nasal ale
CNS (mild mental retardation) 15%

Question 17

Buschke Ollendorff

Answer 17

Buschke-Ollendorff
Dermatofibrosis lenticularis disseminata (multiple elastomas) - skin coloured to yellow dermal papules with/without coalesced plaques often with symmetric distribution on trunk, buttocks, arms
Osteopoikilosis: 1-10mm round to oval opacities within carapal, tarsal bones and phalanges of the hands and feet, pelvis and epiphyses and metaphysis of long bones
RIsk of deafness, sarcomatous change

Question 18

Buschke-Ollendorff 
Inheritance
Age at presentation
Pathogenesis
Key features 
DDx
Lab data
Prognosis

Answer 18

AD, Gene locus unknown
Birth to adulthood
Increased elastic fibre content in the skin; elastin mRNA levels in fibroblast cultures increased. Unknown defect linking bone and skin
DDx: TS, pseudoxanthoma elasticum, familial cutaneous collagenoma
Lab data: xray hands, feet, knees. Skin biopsy with verhoeff-van Gieson or orcein
Prognosis : normal life span. High penetrance. Variable expression (patients may have bone, skin or both in same family).

Question 19

PXE
Inheritance
Age at presentation
DDx
Lab data

Answer 19

AR (most common), AD: ABCC6 (adenosine triphosphate ATP binding cassette subfamily C member 6); transporter gene.
Age: childhood to 2nd or 3rd decade of life
Ddx: cutis laxa, angioid streaks, sickle cell anaemia, pagets disease, hyperphosphatemia, EDS
Lab data: skin bx (von kossa stain – calcium), verhoeff-van gieson stain (curled elastin fibres), fundoscopy, xray of extremity or abdomen if sx
Prognosis: shortened life span secondary to CV complications

Question 20

PXE

Answer 20

Skin : yellow papules, coalescing to plaques overlying redundant, lax, soft skin folds on sides of the neck, axillae, antecubital fossae, abdomen, groin, thighs.
Mucous membranes: yellow papules on labial mucosa, soft palatae, rectal and vaginal mucosa
Eyes: angioid streaks (ruptures in bruch’s membrane),retinal haemorrhage
CV: gastric artery haemorrhage, with epistaxis, haematemesis, claudication, decreased/absent peripheral pulses, hypertension, angina pectoris, MI, CVA mitral valve prolapse
Obstetrics – increased risk of 1st trimester miscarriage, increased CV complications

Question 21

Cutis laxa 
Inheritance
Age at presentation
Pathogenesis 
DDx
Lab data 
Prognosis

Answer 21

AR (most common) fibulin 5 gene, AD (elastin), X linked recessive (ATP7A)
Birth to infancy
Mutations in fibulin 5 gene, elastin or ATP7A gene that impairs Cu transport for lysyl oxidase and normal elastin production
DDx: PXE, EDS, granulomatous slack skin, debars syndrome, SCARF
Lab: skin Bx (fragmented elastic fibres with verhoeff-van geison), serum copper and ceruloplasmin, CXray
Prognosis: varies. If hypoplastic lungs – bad, if skin only ok.

Question 22

Clinical features of Ehlers-Danlos

2nd 3 types

Answer 22

Kyphoscoliosis (VI): Hyperextensible and fragile skin, neonatal hypotonia, joint hypermobility, congenital scoliosis, ocular fragility
Arthrochalasia: Hyperextensible and fragile skin, severe joint hypermobility with congenital bilateral hip dislocation, scoliosis
Dermatosparaxis: Severe skin fragility, sagging and redundant skin that is soft and doughy, easy bruising, hernias, distinctive facies

Question 23

Clinical features of Ehlers Danlos

First 3 types

Answer 23

Classical: Hyperextensible skin, joint hypermobility, atrophic scars, easy bruising, absence of the inferior labial and lingual frenula
Hypermobility: Joint hypermobility, pain and dislocations; absence of inferior labial and lingual frenula
Vascular: Thin, translucent skin; arterial, gastrointestinal and uterine rupture; excessive bruising, small joint hypermobility, characteristic facies