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INTRODUCTION
Heritable connective tissue diseases manifest with a broad range of phenotypic abnormalities, including variable degrees of cutaneous and extracutaneous involvement. At one end of the spectrum, the clinical findings are mild and may be limited to the skin, while in other patients the cutaneous manifestations are part of multi-organ pathology with considerable morbidity and even mortality. There have been significant advances in understanding the molecular bases of heritable disorders of connective tissue. This has led to improved classification and prognostication, with better recognition of the phenotypic spectra and relationships among disorders.
Connective tissue is critical for organogenesis during embryonic development and homeostatic maintenance of tissues, with complex protein assembly and cellโmatrix interactions. The principal fibrillar components of the extracellular matrix (ECM) of the skin are networks consisting of collagen and elastic fibers (see Ch. 95). The study of heritable disorders of connective tissue has demonstrated the considerable impact of disruption of various individual components of the ECM and related proteins.
Classic, โprimaryโ heritable disorders of connective tissue caused by mutations (pathogenic variants) in the genes encoding collagen and structural components of elastic fibers include several forms of EhlersโDanlos syndrome (EDS) and cutis laxa, respectively. In addition to defects in the genes that encode these structural proteins and enzymes that modify them, seemingly unrelated pathologic processes can perturb the ECM. Examples of the latter, which can be considered as โsecondaryโ connective tissue disorders, include pseudoxanthoma elasticum (PXE) and homocystinuria.
This chapter provides a detailed review of EDS, PXE, and cutis laxa. In addition, Marfan syndrome, homocystinuria, osteogenesis imperfecta, and BuschkeโOllendorff syndrome are presented in Table 97.1. These and other genetic diseases that affect the ECM of the skin are also summarized in Table 95.5.
Table 97.1 Additional heritable disorders of connective tissue with cutaneous findings. Other rare genetic diseases of the extracellular matrix are listed in Tableย 95.5. AD, autosomal dominant; AR, autosomal recessive.