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168: Hereditary Disorders of Connective Tissue

Maureen Murphy-Ryan; Noralane Lindor

Key Points

  • Disease summary:

    • 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.

  • Hereditary basis:

    • 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.

Table 168-1Genetic Differential Diagnosis
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Table 168-1 Genetic Differential Diagnosis
Syndrome Gene Symbol Associated Findingsa

Familial abdominal aortic aneurysms

COL3A1 (AD), loci 19q13, 4q31, 9p21

Abdominal aortic aneurysm

Arterial tortuosity syndrome

SLC2A10 (AR)

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

Cutis laxa

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 ...

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