Table 1.
Mendelian Diseases Associated with Spontaneous Pneumothorax
| Condition/Inheritance Pattern | Pulmonary Features (In Addition to Pneumothorax) | Extrapulmonary Features | Penetrance (PTX/Cysts) | Gene(s) | Diagnostic Criteria |
|---|---|---|---|---|---|
| Syndromes resulting from mutated tumor suppressor genes | |||||
| Birt-Hogg-Dubé syndrome, AD | Cysts: elliptical or lentiform, with predominantly basilar, medial, and subpleural distribution | Skin lesions: fibrofolliculomas, trichodiscomas, acrochordons (skin tags) | P: 22–41% | FLCN | 29 |
| Renal cancer: renal cell carcinomas, oncocytomas, and others | C: 83–100% | ||||
| Tuberous sclerosis complex, AD | LAM: cysts, bullae, reticulonodular infiltrates, pleural effusions, obstructive physiology; female predominance | Brain: subependymal nodules, cortical dysplasia (tubers), cerebral white matter migration lines, subependymal giant cell astrocytomas, seizures or infantile spasms, developmental delay/intellectual disability, autism, ADHD | In LAM: | TSC2 | 168 |
| Micronodular pneumocyte hyperplasia | Skin: hypopigmented macules (ash leaf spots), Shagreen patches, confetti lesions, facial angiofibromas, fibrous cephalic plaques, ungual fibromas | P: 56–66% | TSC1 | ||
| Kidney: angiomyolipomas (renal or extrarenal), renal cysts, renal cell carcinomas, oncocytomas | C: ∼100% | ||||
| Heart: rhabdomyomas, arrhythmias | |||||
| Eye: retinal nodular hamartomas, achromic retinal patches | |||||
| Mouth: dental pits, intraoral fibromas | |||||
| Syndromes of disordered connective tissue | |||||
| Marfan syndrome, AD | Lungs usually normal; rare features include: | Skeletal: tall, thin habitus, decreased upper:lower segment ratio, reduced elbow extension, arachnodactyly, hand/wrist signs, pectus excavatum/carinatum, scoliosis/kyphosis, hindfoot deformity, flat feet | P: 4–11% | FBN1 | 170 |
| Cysts | Facial features: dolichocephaly, down-slanting palpebral fissures, enophthalmos, retrognathia, malar hypoplasia | C: 10% (bullae/blebs) | |||
| Emphysema | Eye: lens dislocation, severe myopia | ||||
| Congenital lung malformations | Skin: striae | ||||
| Increased TLC and RV | Cardiac: aortic dilation/dissection/aneurysm/rupture, mitral valve prolapse | ||||
| Vascular (type IV) Ehlers-Danlos syndrome, AD | Cavitary lesions | Vascular: arterial aneurysm, dissection, rupture, carotid–cavernous sinus fistula | P: 16–80% | COL3A1 | 94 |
| Cysts, bullae | Organ rupture: of colon or gravid uterus | ||||
| Fibrous nodules with osseous metaplasia | Facial appearance: thin lips and nose, micrognathia, prominent eyes | ||||
| Hemopneumothorax or pulmonary hemorrhage | Skin: translucent skin with visible veins, easy bruising | ||||
| Orthopedic: clubfoot, congenital hip dislocation, lax small joints, muscle/tendon rupture | |||||
| Loeys-Dietz syndrome, AD | N/A | Vascular: arterial aneurysms, dissection, tortuosity | Unknown | TGFBR1 | None |
| Skeletal: pectus excavatum or carinatum, joint laxity or contractures, cervical spine instability, scoliosis, arachnodactyly, club foot | TGFBR2 | ||||
| Craniofacial: bifid uvula or cleft palate, hypertelorism, retrognathia | SMAD3 | ||||
| Cutaneous: translucent or dystrophic skin, easy bruising | TGFB2 | ||||
| Uterine rupture | TGFB3 | ||||
| SMAD2 | |||||
| Homocystinuria, AR | N/A | Skeletal: Marfanoid habitus | Unknown | CBS | 171 |
| Eye: dislocated lens, myopia | |||||
| Neurologic: intellectual disability, seizures | |||||
| Vascular: thrombosis | |||||
| Cutis laxa,* AD/AR | Bronchiectasis | Cutaneous: redundant, loose, hypoelastic skin | Unknown | ELN | N/A |
| Emphysema | Facial: aged appearance | FBLN4 | |||
| Vascular: aortic aneurysms, tortuosity | FBLN5 | ||||
| Musculoskeletal: joint laxity, scoliosis | LTBP4 | ||||
| Other: hernias | |||||
| Syndromes that disrupt lung architecture | |||||
| Alpha-1 antitrypsin deficiency, AR | Panacinar emphysema | Liver: cirrhosis, hepatocellular carcinoma, neonatal cholestatic jaundice | Unknown | SERPINA1 | 172 |
| Bullae | Skin: panniculitis | ||||
| Bronchiectasis | Inflammatory: vasculitis | ||||
| Obstruction | |||||
| Cystic fibrosis, AR | Bronchiectasis | Gastrointestinal: meconium ileus, pancreatic insufficiency, pancreatitis, malabsorption, failure to thrive | P: 8% | CFTR | 173 |
| Bacterial colonization/infection | Male infertility | ||||
| Cysts/cavitations obstruction respiratory failure | Ear/nose/throat: nasal polyps, sinus disease |
Definition of abbreviations: AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; AR = autosomal recessive; C = cysts; LAM = lymphangioleiomyomatosis; N/A = not applicable; P or PTX = pneumothorax; RV = residual volume.
*
Note that features vary by subtype.