Hereditary disorders of connective tissue (HDCT) are a group of disorders in which genetic errors affect the proper formation of connective tissue, the intercellular material that holds human tissues together.
Connective tissue is a complex network of substances (including collagen, elastin, fibrillin, fibulin, and many others) produced by fibroblast cells. The specific combination and proportion of these elements differs from one tissue to another to create diverse mechanical properties and functions within the human body.
There is extensive overlap both clinically and genetically between the HDCT. A single gene can affect the connective tissue of multiple organ systems (pleiotropy). The clinical features often overlap with other connective disorders caused by mutations in different genes. Furthermore, a single gene may be linked to multiple distinct disorders based on the mutation type and genetic environment.
The ability to differentiate between the 40+ known HDCT has the capacity to significantly alter patient care.
The hereditary basis of HDCT varies by disorder, and can include autosomal recessive, autosomal dominant, X-linked, and de novo mutations. Refer to Table 168-1 for syndrome- and gene-specific details.
Differential diagnosis: Many different clinical findings may spur consideration of an underlying HDCT. Some of the most common findings are joint laxity, skin hyper- or inelasticity, vascular aneurysms, hernias, long bone overgrowth, and ophthalmologic pathology. The differential diagnosis for a suspected HDCT is not easily summarized. The major entities and causative genes and inheritance patterns are summarized in Table 168-1.
|Syndrome||Gene Symbol||Associated Findingsa|
Familial abdominal aortic aneurysms
COL3A1 (AD), loci 19q13, 4q31, 9p21
Abdominal aortic aneurysm
Arterial tortuosity syndrome
Generalized tortuosity of the arterial bed including aorta, arterial stenosis, abdominal aortic aneurysm, aneurysm of medium-sized arteries, ascending aortic dilatation, macrocephaly, characteristic facies, high-arched palate, micrognathia, keratoconus, inguinal and diaphragmatic hernias, intestinal elongation, joint laxity, joint contractures, muscular hypotonia, hyperelastic skin
Bicuspid aortic valve with thoracic aortic aneurysms
NOTCH1, KCNJ2, others (AD)
Ascending aortic dilatation, bicuspid aortic valve, aortic valve calcification
Congenital contractural arachnodactyly
FBN2 (AD), unknown locus heterogeneity
Ascending aortic dilatation, mitral valve prolapse, cranial abnormality, ear dysmorphism “crumpled” with folded upper helix, high-arched palate, retro/micrognathia, keratoconus, myopia, arachnodactyly, joint contractions of knees and ankles that may improve with age, flexion contractures of small digital joints, hip contractures, thumb adduction, clubfoot, paradoxical patellar laxity, pyeloureteral junction stenosis, “marfanoid habitus,” motor developmental delay, muscular hypoplasia, osteopenia/osteoporosis/fractures, pectus deformities, scoliosis, protrusio acetabuli, striae
ELN (AD), FBLN5 (AD, AR-type 1), FBLN4 (AR-type 1), ATP6V0A2 (AR-type 2), P5CS (AR-type 2), PYCR1 (AR-type 2), ATP7A (X-linked)
Generally: loose, redundant, inelastic skin, ascending aortic dilatation, medium vessel aneurysms, arterial tortuosity, enlarged anterior fontanel, hernias, diverticula, lung abnormalities, visceral prolapse, joint laxity or contractures, motor development delay, muscular hypotonia, osteopenia/osteoporosis/fractures (bone fragility), intellectual impairment/developmental delay
AD: TAA, inguinal hernia, emphysema
AR1: infantile emphysema, supravalvular aortic stenosis
AR2: characteristic facies, variable CNS involvement, microcephaly, skin features attenuate with age, neurologic symptoms emerge or worsen with age, late closure of large anterior fontanel
X-linked: occipital bony abnormalities (bilateral, symmetric wedge-shaped bony outgrowths beside the foramen magnum at the site of muscle attachment), failure to thrive due to chronic diarrhea, malabsorption, congenital hydronephrosis or urethral and bladder diverticula.
Familial ectopia lentis
ADAMTSL4 (AR), FBN1 (AD), LTBP-2 (AR), TGFBR2 (AD)
Lens dislocation, secondary glaucoma, myopia, mild skeletal symptoms, mitral valve prolapse, nonprogressive aortic root
Ehlers-Danlos, arthrochalasia type
COL1A1 (AD), COL1A2 (AD)
Early-onset congenital hip dislocation, hernias, extreme joint laxity, osteopenia/osteoporosis/fractures, pectus deformities, scoliosis, short stature, mildly hyperelastic skin, frequent fractures
Ehlers-Danlos, cardiac valvular type
Mitral valve prolapse, hernias, joint laxity, atrophic scars/delayed wound healing, easy bruising, hyperelastic skin
Ehlers-Danlos, classical type
COL5A1 (AD), COL5A2 (AD), COL1A1 (AD)
Ascending aortic dilatation, mitral valve prolapse, joint laxity, pectus deformities/scoliosis, atrophic scars/delayed wound healing, easy bruising, hyperelastic skin, skin that is smooth, velvety, thin, fragile, translucent, and/or atrophic with cigarette paper scarring, characteristic facies (epicanthic folds, excess eyelid skin, prematurely aged appearance)
Ehlers-Danlos, dermatosparaxis type
Enlarged anterior fontanel, delayed phenotype onset, characteristic facies (eyelid fullness, epicanthal folds, downslanting palpebral fissures), retro/micrognathia, hernias, hollow organ rupture, joint laxity, short stature, extreme skin fragility, dental abnormalities, blue sclera, easy bruising, hyperelastic skin
Ehlers-Danlos, kyphoscoliotic type
Ascending aortic dilatation, joint laxity, gross motor development delay, muscular hypotonia, generalized muscle weakness, pectus deformities/scoliosis, hyperelastic skin, “marfanoid” habitus, normal neuromuscular testing, deficient lysyl hydroxylase activity
Ehlers Danlos, musculocontractural type
Distinctive craniofacial dysmorphism, congenital contractures of fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, thin and hyperextensible skin, easy bruising, atrophic scarring, wrinkled palms, joint laxity, ocular involvement (anterior chamber abnormality, blue sclera), large anterior fontanel with delayed closure, normal lysyl hydroxylase activity
Ehlers-Danlos, progeroid type
Characteristic progeroid facies, joint laxity, osteopenia/osteoporosis/fractures, pectus deformities/scoliosis, short stature, intellectual impairment/developmental delay, atrophic scars/delayed wound healing, easy bruising, loose yet hyperelastic skin