Clinical Manifestations of Rare Connective Tissue Disorders

Musculoskeletal and Vascular Manifestations

Musculoskeletal pain and weakness are common complaints that should be carefully elicited, along with morning stiffness, according to the American Thoracic Society 1, 2
Raynaud's phenomenon is one of the most common clinical manifestations, particularly in mixed connective tissue disease and systemic sclerosis, as noted by the American Thoracic Society 2
Photosensitivity may be present in certain subtypes, as reported by the American Thoracic Society 1, 2

Progressive dyspnea on exertion is the most prominent and disabling symptom when interstitial lung disease develops, typically present for >6 months before presentation, according to the American Thoracic Society 1, 2
Nonproductive cough occurs in 40-50% of patients and may be paroxysmal, dry, and refractory to antitussive agents, as noted by the American Thoracic Society 1 and the American College of Chest Physicians 3
Fatigue, cough, or dyspnea on exertion are nonspecific symptoms that may hide behind other organ involvement or associated comorbidities like myopathy or cardiac disease, as reported by the European League Against Rheumatism 4, 5
Early but irreversible lung function loss can occur asymptomatically, making respiratory symptoms particularly concerning, according to the European League Against Rheumatism 4, 5

Dry skin, eczema, and dystrophic nails with rapid nail growth are common, as noted by the American Academy of Pediatrics 6
Sparse or abnormal hair growth including wavy or curly scalp hair with sparse hair at temples, and sparse eyebrows (only 10% have normal eyebrows), as reported by the American Academy of Pediatrics 6
Hyperpigmentation and numerous acquired melanocytic nevi are striking features, with individuals potentially developing over 100 nevi as they age, according to the American Academy of Pediatrics 6
Keratosis pilaris (follicular hyperkeratosis of extremities and/or face) is seen in the majority of cases, as noted by the American Academy of Pediatrics 6

Weight loss, malaise, and fatigue may be noted, though fever is rare and suggests an alternative diagnosis, as reported by the American Thoracic Society 1, 2
Hypertrophic cardiomyopathy can occur in nearly 40% of individuals with cardio-facio-cutaneous syndrome, sometimes rapidly progressive and even resulting in death, according to the American Academy of Pediatrics 6

Intellectual disability is present in 90-100% of individuals with certain rare subtypes like cardio-facio-cutaneous syndrome, as noted by the American Academy of Pediatrics 6
Seizures may occur and are often refractory to medications, requiring multiple anticonvulsants, according to the American Academy of Pediatrics 6
Gross motor delays tend to be more pronounced in early years, with mean age of independent walking around 3 years in affected individuals, as reported by the American Academy of Pediatrics 6

Dry eyes should be carefully elicited as part of Sjögren's overlap features, as noted by the American Thoracic Society 1, 2
"Velcro" crackles on chest auscultation are detected in >80% of patients with interstitial lung disease, typically dry, end-inspiratory, and most prevalent in lung bases, according to the American Thoracic Society 1, 2
Clubbing is noted in 25-50% of patients with progressive pulmonary involvement, as reported by the American Thoracic Society 1, 2

Do not dismiss nonspecific symptoms like fatigue, mild dyspnea, or arthralgias as benign, as early but irreversible organ damage (particularly lung fibrosis) can occur asymptomatically in the first 5-7 years after disease onset, and maintaining high clinical suspicion for interstitial lung disease is essential even when systemic symptoms appear mild, as noted by the European League Against Rheumatism 4, 5