Congenital cutis laxa is a rare inherited connective tissue disorder manifested by inelastic, loose, pendulous skin, giving the appearance of premature aging.
GENETICS/BASIC DEFECTS
1. Genetic heterogeneity
a. Autosomal recessive cutis laxa: the most common type
i. Type I autosomal recessive cutis laxa: less fre- quent than type II
ii. Type II autosomal recessive cutis laxa b. Autosomal dominant cutis laxa
c. X-liked recessive cutis laxa
i. Previously called occipital horn syndrome ii. At present, best termed as Ehlers-Danlos syn-
drome type IX
2. Biochemical and molecular defects
a. Autosomal recessive cutis laxa type I: molecular studies in a large consanguineous Turkish family demon- strated the presence of a homozygous missense muta- tion (T998C) in the fibulin-5 (FBLN5) gene, resulting in a serine-to-proline (S227P) substitution in the fourth calcium-binding epidermal growth factor-like domain of fibulin-5 protein
b. Autosomal dominant cutis laxa
i. Can be caused by mutations in the elastin gene ii. Molecular heterogeneity cannot be excluded c. X-linked recessive cutis laxa
i. Caused by mutations in the ATP7A gene ii. Characterized by diminished activity of lysyl
oxidase in the skin from affected males
iii. Reduced serum copper and ceruloplasmin in affected males, suggesting that the lysyl oxidase deficiency may be secondary to a defect in copper metabolism
iv. Now known to be allelic to Menkes disease
CLINICAL FEATURES
1. Autosomal recessive cutis laxa
a. More common than the autosomal dominant form b. Autosomal recessive cutis laxa type I
i. The poorest prognosis ii. Pulmonary emphysema iii. Umbilical and inguinal hernias
iv. Gastrointestinal and vesicourinary tract diverticuli c. Autosomal recessive cutis laxa type II, also called cutis laxa with joint laxity and developmental delay d. Characteristic facies
i. Appearing aged due to accentuation of skin folds ii. Downward slanting palpebral fissures
iii. Blepharochalasis and, at times, ectropion, adding to the aged appearance
iv. A broad flat nose v. Sagging cheeks vi. Long upper lip vii. Short columella viii. Large ears e. Skin
i. Prominent skin folds (loose skin) around the knees, abdomen, and thighs
ii. No hyperelasticity, fragility, or difficulty in wound healing
f. Skeletal muscular abnormalities i. Dislocation of the hips ii. Joint hyperextensibility iii. Hernia
iv. Osteoporosis
g. Cardiopulmonary abnormalities
i. Severe pulmonary emphysema resulting from generalized elastolysis
a) Tachypnea b) Pneumonitis c) Airway obstruction d) Severe hypoxia e) Respiratory failure ii. Cardiac abnormalities
a) Right ventricular enlargement b) Cor pulmonale
c) Bundle branch block
d) Pulmonary artery hypoplasia and stenosis e) Dilated and tortuous carotid, vertebral, and
pulmonary arteries f) Aortic aneurysm h. Other abnormalities
i. Hernias a) Inguinal b) Diaphragmatic c) Ventral d) Inguinal
ii. Hollow viscus (pharynx, esophagus, and rectum) diverticula
iii. Oral abnormalities
a) Deep and resonant voice secondary to lax vocal cords
b) Loose oral and pharyngeal mucosa iv. Genitourinary abnormalities
a) Bladder diverticula b) Vaginal prolapse v. Dental caries i. A shorter life span
2. Autosomal dominant cutis laxa
a. A relatively benign disorder and less common than the autosomal recessive form
b. Cutaneous laxity
c. Clinical features presenting in infancy 207
i. Intrauterine growth retardation ii. Delayed fontanelle closure iii. Ligamental laxity
iv. Episodes of edema may precede the skin changes, usually within the first 2 months of life v. Aging appearance by the end of the second year vi. Pulmonary emphysema common due to a loss of
elastic tissue in the lungs d. Skin changes presenting in adulthood
i. Usually no internal defects ii. Having a normal life expectancy e. Aging appearance
i. Drooping of eyelids ii. Sagging facial skin
iii. Accentuation of the nasolabial and other facial folds
iv. Often hooked nose with everted nostrils v. Long philtrum
f. Few complications i. Hoarseness
ii. Pulmonary artery stenosis iii. Mitral valve prolapse
iv. Hernia v. Bronchiectasis vi. Joint dislocations
vii. Tortuosity and dilatation of carotid arteries and aorta
viii. Dilatation of sinuses of Valsalva ix. Coarctation of the aorta
g. Normal life span 3. X-linked recessive cutis laxa
a. Long and thin face, neck, and trunk
b. Mild hyperelastic (but not lax) and bruisable skin with resultant atrophic scars
c. Musculoskeletal abnormalities
i. Inferior cranial spurs (occipital horns) a) A constant feature
b) May be palpated
c) May become larger with age
d) May represent ectopic bone formation within the trapezius and sternocleidomastoid aponeur- oses
ii. Skeletal dysplasia most prominent at the wrists and elbows
iii. Limitation of extension of the elbows, shoulders, knees
iv. Hypermobility of the finger joints v. Pes planus
vi. Genu valga
vii. Pectus excavatum or carinatum (40%)
d. Obstructive uropathy secondary to bladder diverticula with bladder neck obstruction (60–70%)
e. Various hernias (hiatal, femoral, and inguinal) (35%) f. Chronic diarrhea (40%)
4. Differential diagnosis a. Wrinkling skin syndrome
i. A rare autosomal recessive disorder of the con- nective tissue
ii. Wrinkled skin over abdomen and on the dorsum of the hands and feet
iii. Poor skin elasticity in affected areas iv. Increased palmar and plantar creases
v. A prominent venous pattern on the chest vi. Mental retardation
vii. Microcephaly viii. Hypotonia
ix. Musculoskeletal abnormalities b. De Barsey syndrome
i. Cutis laxa (wrinkled atrophic skin) ii. Retarded psychomotor development
iii. Corneal clouding due to degeneration of the tunica elastica of the cornea
iv. Intrauterine growth retardation v. Pseudoathetoid movement vi. Muscular hypotonia
vii. Hypermobility of small joints c. Costello syndrome
i. Nasal papillomata ii. Coarse facies iii. Mental retardation
iv. Growth retardation v. Cutis laxa
d. SCARF syndrome
i. An X-linked recessive disorder ii. Skeletal abnormalities
a) Craniostenosis
b) Enamel hypoplasia, hypocalcification of the teeth
c) Short sternum d) Pectus carinatum
e) Abnormally shaped vertebrae
f) Abnormal modeling of long tubular bones iii. Cutaneous abnormalities
a) Cutis laxa
b) Wide-spaced nipples c) Diastasis recti d) Umbilical hernia iv. Ambiguous genitalia
a) Micropenis
b) Perineal hypospadias
v. Retardation: mild to moderate psychomotor retardation
vi. Facial abnormalities a) Multiple hairwhorls b) Epicanthal folds c) Ptosis
d) High and broad nasal root
e) Low-set and posteriorly rotated ears f) Small chin
DIAGNOSTIC INVESTIGATIONS
1. Radiography
a. Autosomal recessive cutis laxa i. Presence of a variety of hernias
a) Femoral b) Inguinal c) Obturator d) Hiatal
ii. Eventrations of the diaphragm
iii. Rectal and uterine prolapse
iv. Common intrathoracic abnormalities a) Hyperexpansion of the lungs
b) Emphysema which may lead to cor pul- monale and death in childhood
c) Upper airway obstruction caused by exces- sively lax vocal cords, leading to congestive heart failure
d) Frequent peripheral pulmonary artery steno- sis and aortic dilatation
v. Diverticula involving the entire bowel but no functional significance
vi. Diverticula of the urinary tract predisposing to infection or causing obstruction
vii. Arteriographic changes
a) Peripheral pulmonary stenosis b) Dilatation and tortuosity of the aorta c) A peculiar corkscrew appearance of the
peripheral systemic arteries, similar to the arterial changes seen in Menkes syndrome b. X-linked recessive cutis laxa
i. Occipital exostosis (horns) symmetrically located on each side of the foramen magnum
ii. Short clavicles with a widened medullary cavity iii. Hammer-shaped distal extremities
iv. Focal hyperostosis of the femora at sites of ten- don and ligament insertion
v. Carpal fusion involving capitate-hamate and trapezium-trapezoid coalescence (over 50%) vi. Deformation of humerus, radius, ulna, tibia,
fibula (90%) vii. Osteoporosis (70%)
viii. Narrowing of rib cage (65%) ix. Dislocation of radial head (40%)
x. Mild platyspondyly xi. Coxa valga
xii. Flattening of acetabular rooofs
2. Histopathological abnormality: fragmentation and paucity of elastic fibers in the skin
3. X-linked cutis laxa a. Non-molecular testing
i. Low serum copper concentration ii. Low serum ceruloplasmin concentration iii. Copper transport studies in cultured fibroblasts:
impaired cellular copper exodus demonstrated by increased cellular copper retention in pulse- chase experiments with radiolabelled copper iv. Plasma and CSF catecholamine analysis: abnor-
mal levels reflecting partial deficiency of dopamine-beta-hydroxylase, a copper-dependent enzyme critical for catecholamine biosynthesis v. Low activity of a copper-dependent enzyme,
lysyl oxidase b. Molecular genetic testing
i. Mutation analysis: multiplex PCR analysis, available on a clinical basis, to detect large ATP7A deletions
ii. Sequence analysis: direct sequence analysis of the ATP7A coding region and flanking intron sequences, available on a clinical basis
iii. Mutation scanning: heteroduplex analysis, avail- able on a clinical basis, to detect small mutations
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Autosomal recessive cutis laxa: 25%
ii. Autosomal dominant cutis laxa: not increased unless a parent is affected
iii. X-linked recessive cutis laxa:
a) When the mother is a carrier: 50% risk of brother will be affected and 50% of sisters carriers
b) When mother is not a carrier: the recurrence risk is low but greater than that for the gen- eral population because the risk of germline mosaicism in mother is not known
b. Patient’s offspring
i. Autosomal recessive cutis laxa: not increased unless the spouse is a carrier or affected ii. Autosomal dominant cutis laxa: 50%
iii. X-linked recessive cutis laxa: Males with occip- ital horn syndrome will pass the disease-causing gene to all of their daughters and none of their sons
2. Prenatal diagnosis
a. DNA-based analysis on fetal DNA obtained from amniocentesis or CVS for the previously character- ized disease-causing mutation
b. Fetal sex determination for X-linked recessive cutis laxa (occipital horn syndrome)
3. Management
a. Supportive therapy: antibiotic prophylaxis for bladder infection
b. Surgery for bladder diverticula
c. Plastic surgery to improve aging appearance i. Serial excisions of the skin
ii. Blepharoplasty iii. Rhytidectomy
iv. Rhinoplasty
v. Shortening of the upper lip vi. Earlobe reduction
vii. Neck lift
viii. Correction of lower eyelid laxity, epiphora, and upper eyelid ptosis
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Fig. 3. A 10-year-old girl with cutis laxa showing redundancy of the skin, sagging of the upper lids, short columella, long philtrum, and sagging skin folds over trunk.
Fig. 1. An infant with cutis laxa showing redundancy of skin folds and bilateral hernias.
Fig. 2. A young girl with cutis laxa showing redundancy of the skin folds, short columella, long philtrum, and sagging of the lower chin and prominent loose skin folds of the trunk.
