Clinical characteristics: LTBP4-related cutis laxa is characterized by cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, and other evidence of a generalized connective tissue disorder such as inguinal hernias and hollow visceral diverticula (e.g., intestine, bladder). Other manifestations can include pyloric stenosis, diaphragmatic hernia, rectal prolapse, gastrointestinal elongation/tortuosity, cardiovascular abnormality, pulmonary hypertension, hypotonia and frequent pulmonary infections. Bladder diverticula and hydronephrosis are common. Early demise has been associated with pulmonary emphysema.
Diagnosis/testing: The diagnosis of LTBP4-related cutis laxa is established in a proband with cutis laxa and biallelic pathogenic variants in LTBP4.
Management: Treatment of manifestations: Treatment is largely symptomatic and may include: treatment of pulmonary emphysema (inhaled corticosteroids, atropine, and selective β2-adrenergic bronchodilation, and supplemental oxygen as needed) medical or surgical treatment for gastrointestinal issues; education on complete bladder emptying when voiding; and treatment of clinically relevant pulmonary artery stenosis and pulmonary hypertension; physical therapy for muscle strength and stability. Routine immunizations against respiratory infections is important.
Surveillance: Yearly assessment of pulmonary function and oxygenation and repeat imaging of the GI tract, urinary tract, and cardiovascular system.
Agents/circumstances to avoid: Positive pressure ventilation (unless needed to treat life-threatening conditions); exposure to people with respiratory infections; tobacco smoking, which can result in rapid severe loss of lung function; isometric exercise and contact sports or activities that increase the risk for blunt abdominal trauma and/or joint injury or pain; sunbathing or tanning to preserve any residual skin elasticity.
Genetic counseling: LTBP4-related cutis laxa is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an LTBP4 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the LTBP4 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing, and preimplantation genetic testing for LTBP4-related cutis laxa are possible.
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