Chapter 72 - Genetic Disorders Affecting Dermal Connective Tissue

Question 1

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Hyperextensible skin; easy bruising; wide, atrophic scars; hypermobile joints

Answer 1

Classical

Question 2

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Similar to cEDS but without atrophic scarring; foot deformities; muscle weakness; acrogeria; axonal polyneuropathy

Answer 2

Classical-like EDS

Question 3

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Similar to cEDS but with severe, progressive, cardiac valvular disease

Answer 3

Cardiac-valvular EDS

Question 4

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Thin, translucent skin with easy bruising; arterial and visceral rupture; typical facies

Answer 4

Vascular EDS

Question 5

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Smooth, velvety skin; joint hypermobility

Answer 5

Hypermobile EDS

Question 6

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Hyperextensible and fragile skin; severe joint hypermobility; congenital hip dislocation

Answer 6

Arthrochalasia EDS

Question 7

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Severely fragile, sagging, redundant skin; hernias and premature rupture of fetal membranes

Answer 7

Dermatosparaxis EDS

Question 8

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Atrophic scars, easy bruising; neonatal hypotonia; scoliosis; ocular rupture; marfanoid habitus

Answer 8

Kyphoscoliotic EDS

Question 9

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Thin cornea; early-onset progressive keratoconus/ keratoglobus; blue sclerae; corneal scarring; retinal detachment; deafness; developmental hip dysplasia; scoliosis; arachnodactyly; distal joint hypermobility; soft, velvety, thin skin

Answer 9

Brittle cornea syndrome

Question 10

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Progressive short stature; variable muscle hypotonia; limb bowing; hyperextensible skin; delayed motor and cognitive development; osteopenia; characteristic radiographic findings

Answer 10

Spondylodysplastic EDS

Question 11

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Congenital multiple contractures; characteristic craniofacial features; skin hyperextensibility; easy bruising; skin fragility with atrophic scars; increased palmar wrinkling; recurrent/chronic dislocations; chronic constipation and colonic diverticula; pneumothorax/pneumohemothorax

Answer 11

Musculocontractural EDS

Question 12

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Congenital muscle hypotonia and/or atrophy improving with age; proximal joint contractures; distal joint hypermobility; soft, doughy skin with atrophic scarring; motor developmental delay with myopathy on biopsy

Answer 12

Myopathic EDS

Question 13

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

CLINICAL EDS SUBTYPE

CLINICAL FEATURES
Severe, intractable, early-onset periodontitis; gingival detachment; pretibial plaques; family history; easy bruising; distal joint hypermobility; skin hyperextensibility, fragility, abnormal scarring (wide/atrophic); increased rate of infections; marfanoid facial features; acrogeria; prominent vasculature

Answer 13

Periodontal EDS

Question 14

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Classical

Answer 14

AD

Question 15

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Classical-like EDS

Answer 15

AR

Question 16

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Cardiac-valvular EDS

Answer 16

AR

Question 17

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Vascular EDS

Answer 17

AD

Question 18

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Hypermobile EDS

Answer 18

AD/AR

Question 19

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Arthrochalasia EDS

Answer 19

AD

Question 20

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Dermatosparaxis EDS

Answer 20

AR

Question 21

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Kyphoscoliotic EDS

Answer 21

AR

Question 22

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Brittle cornea syndrome

Answer 22

AR

Question 23

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Spondylodysplastic EDS

Answer 23

AR

Question 24

TABLE 72-1
The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects

INHERITANCE

CLINICAL EDS SUBTYPE
Musculocontractural EDS

Answer 24

AR

Question 25

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects INHERITANCE CLINICAL EDS SUBTYPE Myopathic EDS

Answer 25

AD/AR

Question 26

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects INHERITANCE CLINICAL EDS SUBTYPE Periodontal EDS

Answer 26

AD

Question 27

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Classical

Answer 27

Collagen Type V/(COL5A1, COL5A2)

Question 28

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Classical-like EDS

Answer 28

Tenascin XB/(TNXB)

Question 29

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Cardiac-valvular EDS

Answer 29

Type I collagen/(COL1A2—biallelic mutations leading to nonsense-mediated messenger RNA decay and loss of pro a2(I) collagen chains

Question 30

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Vascular EDS

Answer 30

Major: collagen Type III/(COL3A1) Rare: Type I collagen/(COL1A1: c.934C>T, p.[Arg312 Cys]; c.1720C>T, p.[Arg574Cys]; c.3227C>T, p.[Arg1093Cys])

Question 31

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Hypermobile EDS

Answer 31

Unclear for most; collagen Type III; tenascin XB/(COL3A1; TNXB)a

Question 32

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Arthrochalasia EDS

Answer 32

Collagen Type I/(COL1A1; COL1A2)

Question 33

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Dermatosparaxis EDS

Answer 33

Procollagen I N-peptidase/(ADAMTS2)

Question 34

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Kyphoscoliotic EDS

Answer 34

Lysyl hydroxylase/(PLOD1) FKBP22/(FKBP14)

Question 35

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Brittle cornea syndrome

Answer 35

ZNF469/(ZNF469) PRDM5/(PRDM5)

Question 36

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Spondylodysplastic EDS

Answer 36

B4GalT7/(B4GALT7) B3GalT6/(B3GALT6) ZIP13/(SLC39A13)

Question 37

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Musculocontractural EDS

Answer 37

D4ST1/(CHST14) DSE/(DSE)

Question 38

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Myopathic EDS

Answer 38

Type XII collagen/(COL12A1)

Question 39

TABLE 72-1 The Ehlers-Danlos Syndromes: Clinical Subtypes and Associated Defects PROTEIN/(GENE DEFECT) CLINICAL EDS SUBTYPE Periodontal EDS

Answer 39

C1r/(C1R) C1s/(C1S)

Question 40

TABLE 72-3 Criteria for Skin Hyperextensibility 1. Pinch and lift the skin, pulling until resistance is met. _____ is present if the skin can be stretched beyond 2. _____ on distal forearms and/or dorsal hands 3. _____ at neck, elbow, and/or knees

Answer 40

1. Pinch and lift the skin*, pulling until resistance is met. Hyperextensibility is present if the skin can be stretched beyond *Best assessed at a site not subjected to mechanical forces or scarring, such as the volar surface of the nondominant forearm. 2. 1.5 cm on distal forearms and/or dorsal hands 3. 3 cm at neck, elbow, and/or knees

Question 41

TABLE 72-4 Beighton Criteria for Joint Hypermobility 1. Passive dorsiflexion of the fifth finger _____ degrees. 2. Passive apposition of the _____ to the flexor aspect of the _____ (________ sign). 3. Hyperextension of the elbow _____ degrees. 4. Hyperextension of the knees _____ degrees. 5. Ability of the ______ to completely touch the floor during forward flexion of the trunk with knees fully extended.

Answer 41

1. Passive dorsiflexion of the fifth finger >90 degrees. 2. Passive apposition of the thumbs to the flexor aspect of the forearm (Beighton sign). 3. Hyperextension of the elbow >10 degrees. 4. Hyperextension of the knees >10 degrees. 5. Ability of the palms to completely touch the floor during forward flexion of the trunk with knees fully extended.

Question 42

TABLE 72-4 Beighton Criteria for Joint Hypermobility Numbers ___ to ___ are scored for each side, so that a maximal score of 2 is possible if both left and right sides meet criterion; ___ is scored as 1. A person who scores _____ is hypermobile.

Answer 42

Numbers 1 to 4 are scored for each side, so that a maximal score of 2 is possible if both left and right sides meet criterion; number 5 is scored as 1. A person who scores 5 or greater out of 9 is hypermobile.

Question 43

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Congenital - Primarily cutaneous (hyperextensible loose hanging skin folds) - Hernias - Rare vascular complications - Acute respiratory disease, 55%; emphysema, approximately 35% - (Near-)normal life expectancy - Some clinical variability

Answer 43

ADCL

Question 44

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Mild mental retardation - Exostoses - Congenital wrinkling of the skin (mainly distal) and skin hyperextensibility - Pili torti - Distal joint laxity - Progressive exostoses including “occipital horns” - Skeletal abnormalities - Failure to thrive - Genitourinary (GU) diverticula - Retinal artery tortuosity

Answer 44

XLR

Question 45

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Emphysema - Congenital - Severe - Loose hanging redundant skin - Early lethality - Supravalvular and aortic and Pulmonary artery stenosis - Hernias (various including diaphragmatic) - Mucosal prolapse (Congenital or early onset) - No hip dislocation - GI and GU diverticula with secondary infections - Arterial tortuosity - Aneurysm formation (more common in FBLN4-related CL) - Marfanoid habitus - Osteoporosis (FBLN4) - Diaphragmatic hernia; corneal thinning (SLC2A10)

Answer 45

ARCL Type 1 (including Urban-Rifkin-Davis syndrome [URDS])

Question 46

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES No ocular involvement + abnormal glycosylation = ATP6V subunit mutations

Answer 46

Metabolic CL Type 2 (ARCL)

Question 47

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Clinical variability - Downslanting palpebral fissures - Long philtrum - Microcephaly - Developmental delay - Hypotonia - Congenital hip dislocation - Mental retardation - Delayed fontanel closure - Cobblestone brain malformation - Congenital CL improves over time, especially after puberty - Dental caries common - Cardiopulmonary involvement is very rare - Apolipoprotein C-III isoelectric focusing is diagnostic

Answer 47

ARCL2A ranges from Debre type (severe) to wrinkly skin (mild)

Question 48

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Generalized CL - Dysmorphic facies - Hypotonia - Joint contractures - Congenital hip dysplasia - Cardiac abnormalities - Pneumothorax - Aortic root dilation - Marfanoid habitus - ATP6V1E1 – generalized skin wrinkling - ATP6V1A – larger skin folds/abnormal fat distribution

Answer 48

ARCL2 (ATP6V1E1, ATP6V1A)

Question 49

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Severe phenotype - Neurologic symptoms - Microcephaly - Intrauterine growth retardation (IUGR) - Cholestatic liver disease: elevated transaminases; creatine kinase; bilirubin - Skeletal dysplasia - Cardiac anomalies - Recurrent infections - Hyperthermia - Early fatality

Answer 49

ARCL2 – conserved oligomeric Golgi (COG) 7

Question 50

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Progeroid appearance - Osteopenia - Wormian bones - Variable connective tissue weakness - Wrinkly, lax skin—especially over hands - Finger contractures - Triangular facies with mandibular hypoplasia causing prognathism - Adulthood: long facies with prominent chin - Lipodystrophy - Variable Intellectual disability is common - Agenesis of corpus callosum - Cataracts/corneal clouding - Athetoid movements

Answer 50

ARCL2B (progeroid forms)

Question 51

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - CL - Joint laxity/hypotonia - Microcephaly - Intrauterine and postnatal growth retardation - Congenital hip dislocation - Bilateral subcapsular cataract - Severe mental retardation - Structural brain abnormalities - Progressive neurodegeneration - Seizures - Dystonia (hands/feet) - Peripheral neuropathy - Paradoxical hyperammonemia with hyperprolinemia and urea cycle deficiency in some patients

Answer 51

ARCL Type 3a (ARCL3A)

Question 52

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - CL - Significant mental retardation - Eye anomalies (cataract) - Dystonia - Progeroid features - Progressive - No glycosylation defects

Answer 52

ARCL Type 3b (ARCL3B) - De Barsy syndrome (DBS)

Question 53

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Progeroid features - Malar/maxillary hypoplasia - “Droopy” face: oblique furrows from lateral edge of supraorbital ridge to outer canthus - Sagging cheeks - Joint laxity - Short-stature dwarfism but may be normal weight/length at birth - Normal mental development - Osteoporosis/osteopenia - Frequent fractures, especially vertebral - Improvement in progeroid features and joint laxity over time - No glycosylation defects

Answer 53

Gerodermia osteodysplastica (GO)

Question 54

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Characteristic facial features: puffy eyelids; soft, redundant facial skin; sagged cheeks; lower lip eversion; micrognathia; gingival hypertrophy; abnormal dentition; sparse scalp hair - Macrocephaly - Severe joint laxity - Scoliosis - Normal psychomotor development

Answer 54

MACS/RIN2 syndrome (macrocephaly; alopecia; CL; scoliosis)

Question 55

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Congenital CL in some patients - Cutaneous telangiectasia - Hydrops fetalis - Aortic coarctation - Bleeding tendency - Dysmorphic features - Hypertrichosis - Variable multiorgan involvement - Hepatosplenomegaly - Clitoral enlargement - Cirrhosis - Liver failure - Hemolytic anemia - GU malformation - Renal - Thrombocytopenia - Erythronic acid is novel biomarker of disease - Many exhibit gradual improvement including skin—except for liver and renal

Answer 55

Transaldolase deficiency

Question 56

TABLE 72-9 Cutis Laxa Syndromes: Clinical Subtypes and Associated Defects SUBTYPE CLINICAL FEATURES - Loose, soft doughy skin - Inguinal, axillary, hands/feet - Feeding problems - Pulmonary artery stenosis - Bleeding tendency - Dry skin - Characteristic facies

Answer 56

Costello syndrome; Noonan syndrome; Cardiofaciocutaneous syndrome (115150)