Age PYR DPYR Ratio DPYR/PYR 0-11 months Not applicable Not applicable 0.13-0.20 1-3 years Not applicable Not applicable 0.18-0.24 4-9 years Not applicable Not applicable 0.19-0.25 10-14 years Not applicable Not applicable 0.17-0.27 15-19 years Not applicable Not applicable 0.20-0.26 20 years and older Not applicable Not applicable 0.23- 0.29

Ehlers-Danlos Syndrome (EDS) describes a heterogeneous group of connective tissue disorders. EDS VI, also known as the kyphoscoliotic type, is characterized by hyperextensible skin, joint laxity, progressive scoliosis, severe muscle hypotonia at birth, and ocular fragility. It is caused by a deficiency of the enzyme lysyl hydroxylase. Lysyl hydroxylase is encoded by a gene located on chromosome 1p36.3-p36.2 known as procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1). This enzyme is essential for the hydroxylation of lysine residues on collagen. The derived hydroxylysine residues are the precursors of the most stable crosslinks of collagen, pyridinoline, and deoxypyridinoline. The incidence of EDS VI has been estimated at 1 in 100,000 with a carrier frequency of 1 in 150. It is inherited in an autosomal recessive manner. Although 20 different mutations have been detected in the PLOD1 gene, mutation analysis is only being performed on a research basis. The diagnosis of EDS VI is performed using HPLC to determine the ratio of deoxypyridinoline to pyridinoline in urine. A markedly elevated ratio is indicative of the disease. The diagnosis can be confirmed by enzyme assay in cultured dermal fibroblasts. Affected fetuses are at risk for premature rupture of membranes and 30 percent have clubfoot. Infants usually present with generalized joint laxity and muscle hypotonia. Gross milestones, such as walking, may be delayed. Thoracic scoliosis is common in childhood and often progresses into the moderate to severe range. All affected individuals have hyperelastic skin, 60 percent have abnormally thin wide scarring, and 50 percent experience severe bruising. Most affected individuals have high myopia and microcornea, while a minority have ocular fragility, glaucoma, or retinal detachment. Frequent joint dislocations can also pose a serious problem. Adults with severe kyphoscoliosis may develop frequent pneumonia and restrictive lung disease. Affected individuals are at increased risk for aortic dilation/dissection, as well as rupture of medium-sized arteries. There are no genotypic/phenotypic correlations that have been determined in the few affected individuals whose mutations have been determined. Two pathological variants have been observed in more than one affected family (gene duplication of 7 exons and Y511X). The most sensitive and specific manner to establish a diagnosis of EDS VI remains through biochemical testing. Affected individuals with kyphoscoliosis should be referred for regular follow-up with an orthopedic surgeon. Older children, adolescents, and adults can benefit from a physical therapy regimen to strengthen large muscle groups, particularly the shoulder girdle. They should undergo routine screening for inguinal hernia. Routine ophthalmologic examination may be useful for detection and management of myopia and glaucoma. Referral to a cardiologist for an echocardiogram for aortic root measurement is recommended every five years, even if the initial examination is normal. Antimicrobial prophylaxis for individuals with mitral valve prolapse and aggressive blood pressure control is critical. Affected individuals may also benefit from vitamin C (0.5-10 g per day) to improve muscular strength and wound healing. This test should be offered to individuals with clinical symptoms suggesting EDS VI, such as hyperextensible skin, joint hypermobility, kyphoscoliosis, easy bruisability, or corneal fragility. All siblings of individuals deemed affected should also be tested, since they are at 25 percent risk for the same disease. Carrier testing cannot be performed biochemically or by enzyme assay and is not currently clinically available through PLOD1 mutation analysis. Prenatal diagnosis is only available through laboratories that perform custom DNA analysis for couples who have had a previous affected child with identified mutations. Genetic counseling should be offered to all affected individuals and their parents. The HPLC analysis allows the simultaneous quantitation of pyridinoline and deoxypyridinoline. In patients with EDS VI, the excretion of deoxypyridinoline is markedly increased. As a result, the deoxypyridinoline/pyridinoline ratio is also markedly increased (from 0.2 in normal controls to 4-6 in patients with EDS VI) and allows the diagnosis.