Congenital Cutis Laxa Congenital cutis laxa is a rare inherited connective tissue iv. A broad flat nose disorder manifested by inelastic, loose, pendulous skin, giving v. Sagging cheeks the appearance of premature aging. vi. Long upper lip vii. Short columella GENETICS/BASIC DEFECTS viii. Large ears e. Skin 1. Genetic heterogeneity i. Prominent skin folds (loose skin) around the a. Autosomal recessive cutis laxa: the most common knees, abdomen, and thighs type ii. No hyperelasticity, fragility, or difficulty in wound i. Type I autosomal recessive cutis laxa: less fre- healing quent than type II f. Skeletal muscular abnormalities ii. Type II autosomal recessive cutis laxa i. Dislocation of the hips b. Autosomal dominant cutis laxa ii. Joint hyperextensibility c. X-liked recessive cutis laxa iii. Hernia i. Previously called occipital horn syndrome iv. Osteoporosis ii. At present, best termed as Ehlers-Danlos syn- g. Cardiopulmonary abnormalities drome type IX i. Severe pulmonary emphysema resulting from 2. Biochemical and molecular defects generalized elastolysis a. Autosomal recessive cutis laxa type I: molecular studies a) Tachypnea in a large consanguineous Turkish family demon- b) Pneumonitis strated the presence of a homozygous missense muta- c) Airway obstruction tion (T998C) in the fibulin-5 (FBLN5) gene, resulting d) Severe hypoxia in a serine-to-proline (S227P) substitution in the e) Respiratory failure fourth calcium-binding epidermal growth factor-like ii. Cardiac abnormalities domain of fibulin-5 protein a) Right ventricular enlargement b. Autosomal dominant cutis laxa b) Cor pulmonale i. Can be caused by mutations in the elastin gene c) Bundle branch block ii. Molecular heterogeneity cannot be excluded d) Pulmonary artery hypoplasia and stenosis c. X-linked recessive cutis laxa e) Dilated and tortuous carotid, vertebral, and i. Caused by mutations in the ATP7A gene pulmonary arteries ii. Characterized by diminished activity of lysyl f) Aortic aneurysm oxidase in the skin from affected males h. Other abnormalities iii. Reduced serum copper and ceruloplasmin in i. Hernias affected males, suggesting that the lysyl oxidase a) Inguinal deficiency may be secondary to a defect in copper b) Diaphragmatic metabolism c) Ventral iv. Now known to be allelic to Menkes disease d) Inguinal ii. Hollow viscus (pharynx, esophagus, and rectum) CLINICAL FEATURES diverticula 1. Autosomal recessive cutis laxa iii. Oral abnormalities a. More common than the autosomal dominant form a) Deep and resonant voice secondary to lax b. Autosomal recessive cutis laxa type I vocal cords i. The poorest prognosis b) Loose oral and pharyngeal mucosa ii. Pulmonary emphysema iv. Genitourinary abnormalities iii. Umbilical and inguinal hernias a) Bladder diverticula iv. Gastrointestinal and vesicourinary tract diverticuli b) Vaginal prolapse c. Autosomal recessive cutis laxa type II, also called v. Dental caries cutis laxa with joint laxity and developmental delay i. A shorter life span d. Characteristic facies 2. Autosomal dominant cutis laxa i. Appearing aged due to accentuation of skin folds a. A relatively benign disorder and less common than ii. Downward slanting palpebral fissures the autosomal recessive form iii. Blepharochalasis and, at times, ectropion, adding b. Cutaneous laxity to the aged appearance c. Clinical features presenting in infancy 207 208 CONGENITAL CUTIS LAXA i. Intrauterine growth retardation iii. Poor skin elasticity in affected areas ii. Delayed fontanelle closure iv. Increased palmar and plantar creases iii. Ligamental laxity v. A prominent venous pattern on the chest iv. Episodes of edema may precede the skin vi. Mental retardation changes, usually within the first 2 months of life vii. Microcephaly v. Aging appearance by the end of the second year viii. Hypotonia vi. Pulmonary emphysema common due to a loss of ix. Musculoskeletal abnormalities elastic tissue in the lungs b. De Barsey syndrome d. Skin changes presenting in adulthood i. Cutis laxa (wrinkled atrophic skin) i. Usually no internal defects ii. Retarded psychomotor development ii. Having a normal life expectancy iii. Corneal clouding due to degeneration of the e. Aging appearance tunica elastica of the cornea i. Drooping of eyelids iv. Intrauterine growth retardation ii. Sagging facial skin v. Pseudoathetoid movement iii. Accentuation of the nasolabial and other facial vi. Muscular hypotonia folds vii. Hypermobility of small joints iv. Often hooked nose with everted nostrils c. Costello syndrome v. Long philtrum i. Nasal papillomata f. Few complications ii. Coarse facies i. Hoarseness iii. Mental retardation ii. Pulmonary artery stenosis iv. Growth retardation iii. Mitral valve prolapse v. Cutis laxa iv. Hernia d. SCARF syndrome v. Bronchiectasis i. An X-linked recessive disorder vi. Joint dislocations ii. Skeletal abnormalities vii. Tortuosity and dilatation of carotid arteries and a) Craniostenosis aorta b) Enamel hypoplasia, hypocalcification of the viii. Dilatation of sinuses of Valsalva teeth ix. Coarctation of the aorta c) Short sternum g. Normal life span d) Pectus carinatum 3. X-linked recessive cutis laxa e) Abnormally shaped vertebrae a. Long and thin face, neck, and trunk f) Abnormal modeling of long tubular bones b. Mild hyperelastic (but not lax) and bruisable skin iii. Cutaneous abnormalities with resultant atrophic scars a) Cutis laxa c. Musculoskeletal abnormalities b) Wide-spaced nipples i. Inferior cranial spurs (occipital horns) c) Diastasis recti a) A constant feature d) Umbilical hernia b) May be palpated iv. Ambiguous genitalia c) May become larger with age a) Micropenis d) May represent ectopic bone formation within b) Perineal hypospadias the trapezius and sternocleidomastoid aponeur- v. Retardation: mild to moderate psychomotor oses retardation ii. Skeletal dysplasia most prominent at the wrists vi. Facial abnormalities and elbows a) Multiple hairwhorls iii. Limitation of extension of the elbows, shoulders, b) Epicanthal folds knees c) Ptosis iv. Hypermobility of the finger joints d) High and broad nasal root v. Pes planus e) Low-set and posteriorly rotated ears vi. Genu valga f) Small chin vii. Pectus excavatum or carinatum (40%) d. Obstructive uropathy secondary to bladder diverticula with bladder neck obstruction (60–70%) DIAGNOSTIC INVESTIGATIONS e. Various hernias (hiatal, femoral, and inguinal) (35%) 1. Radiography f. Chronic diarrhea (40%) a. Autosomal recessive cutis laxa 4. Differential diagnosis i. Presence of a variety of hernias a. Wrinkling skin syndrome a) Femoral i. A rare autosomal recessive disorder of the con- b) Inguinal nective tissue c) Obturator ii. Wrinkled skin over abdomen and on the dorsum d) Hiatal of the hands and feet ii. Eventrations of the diaphragm CONGENITAL CUTIS LAXA 209 iii. Rectal and uterine prolapse iii. Mutation scanning: heteroduplex analysis, avail- iv. Common intrathoracic abnormalities able on a clinical basis, to detect small mutations a) Hyperexpansion of the lungs b) Emphysema which may lead to cor pul- GENETIC COUNSELING monale and death in childhood c) Upper airway obstruction caused by exces- 1. Recurrence risk sively lax vocal cords, leading to congestive a. Patient’s sib heart failure i. Autosomal recessive cutis laxa: 25% d) Frequent peripheral pulmonary artery steno- ii. Autosomal dominant cutis laxa: not increased sis and aortic dilatation unless a parent is affected v. Diverticula involving the entire bowel but no iii. X-linked recessive cutis laxa: functional significance a) When the mother is a carrier: 50% risk of vi. Diverticula of the urinary tract predisposing to brother will be affected and 50% of sisters infection or causing obstruction carriers vii. Arteriographic changes b) When mother is not a carrier: the recurrence a) Peripheral pulmonary stenosis risk is low but greater than that for the gen- b) Dilatation and tortuosity of the aorta eral population because the risk of germline c) A peculiar corkscrew appearance of the mosaicism in mother is not known peripheral systemic arteries, similar to the b. Patient’s offspring arterial changes seen in Menkes syndrome i. Autosomal recessive cutis laxa: not increased b. X-linked recessive cutis laxa unless the spouse is a carrier or affected i. Occipital exostosis (horns) symmetrically located ii. Autosomal dominant cutis laxa: 50% on each side of the foramen magnum iii. X-linked recessive cutis laxa: Males with occip- ii. Short clavicles with a widened medullary cavity ital horn syndrome will pass the disease-causing iii. Hammer-shaped distal extremities gene to all of their daughters and none of their iv. Focal hyperostosis of the femora at sites of ten- sons don and ligament insertion 2. Prenatal diagnosis v. Carpal fusion involving capitate-hamate and a. DNA-based analysis on fetal DNA obtained from trapezium-trapezoid coalescence (over 50%) amniocentesis or CVS for the previously character- vi. Deformation of humerus, radius, ulna, tibia, ized disease-causing mutation fibula (90%) b. Fetal sex determination for X-linked recessive cutis vii. Osteoporosis (70%) laxa (occipital horn syndrome) viii. Narrowing of rib cage (65%) 3. Management ix. Dislocation of radial head (40%) a. Supportive therapy: antibiotic prophylaxis for bladder x. Mild platyspondyly infection xi. Coxa valga b. Surgery for bladder diverticula xii. Flattening of acetabular rooofs c. Plastic surgery to improve aging appearance 2. Histopathological abnormality: fragmentation and i. Serial excisions of the skin paucity of elastic fibers in the skin ii. Blepharoplasty