Ehlers-Danlos arthrochalasia type (VIIA-B)--expanding the phenotype: from prenatal life through adulthood

Abstract

The Ehlers-Danlos syndromes (EDS) form a clinically and genetically heterogeneous group of inherited connective-tissue disorders characterized by joint hypermobility, tissue fragility and skin abnormalities. Six subtypes have been well characterized based on clinical features and molecular genetic abnormalities. The arthrochalasia type EDS (formerly types VIIA and B) is characterized by severe generalized joint hypermobility with multiple dislocations including congenital bilateral dislocation of the hips, muscular hypotonia and distinct dysmorphic features. The diagnosis of the arthrochalasia type EDS is of importance in the neonatal period because of consequences of physical disability in later life. However, the differential diagnosis may be difficult because of overlap with other hypermobility syndromes. In addition, the significant hypotonia may direct the physician toward various neuromuscular diagnoses. As patients become older, the hypotonia decreases and facial features become less distinct. In this report, we describe seven patients at different ages. Timing of diagnosis varied from prenatal life to adult age. The diagnosis of EDS type VII was confirmed by biochemical studies or mutation analysis showing characteristic mutations in COL1A1 and COL1A2. These mutations result in skipping of exon 6, which leads to defective collagen synthesis. For physicians treating patients with EDS type VII, achieving mobility for the patient is the greatest challenge and it may be impossible because of recurrent dislocations of nearly all joints in severe cases.

Figure 1

Pedigrees. Pedigrees of all patients and their parents.

Figure 2

Phenotypic features of patient 1. A, muscular hypotonia on day 1 of life; B, hyperlaxity of ankle joints; C, facial features at age 3 months; D, micrognathia; E, hyperlaxity of knee; F, hypotonia and hyperlaxity at age 3 months.

Figure 3

Phenotypic features of patient 2. A, muscular hypotonia on day 1 of life; B, facial features on day 1; C, criss-cross patterning of palms; D, facial features at age 1 year; E, hyperlaxity of feet.

Figure 4

Phenotypic features of patient 3. A, mild muscular hypotonia at age 3 months; B, facial features at age 3 months; C, hands at age 2 years; D, facial features at age 2 years; E, hands at age 2 years; F, full body view at age 5 years.

Figure 5

Patient 4. A, extensive skin laesions, thin skin and deformities of the feet; B, hyperextension of the fifth finger, consistent with extreme laxity of the small joints; C, dislocations of small joints in second finger with swan neck deformity.

Figure 6

Phenotypic features of patients 5, 6 and 7. A, muscular hypotonia and hyperlaxity on day 1 of life in patient 7; B, patient 6 at age 2 years; C, patient 5 at age 25 years; D, patients 6 and 7 at age 4 and 6 years respectively; E – G, abnormal dentition in patients 5, 6 and 7 respectively.

Figure 7

Sequence traces of mutations in the COL1A2 gene from patients 1 - 3. Only reverse sequence are shown, because due to a long T stretch near the 5’ end of exon 6. This exon cannot be sequenced in forward direction. Patient 1: c.279+2T>G. Patient 2: c.226+1A>G. Patient 3: c.279+1G>T. SDS-PAGE analysis of 14C-labeled collagen molecules in dermal fibroblasts from patient 4. Top right figure: collagen medium fraction. Left and right lane: control, middle lane: patient. Top band corresponds to the α1(I) collagen chain, the lowest band corresponds to the α2(I) collagen chain. In the patient there is an additional band, which corresponds to the uncompletely processed pNα2(I) chains, consistent with defective collagen synthesis. Bottom right figure: cell fraction. Similar bands visible. Left lane: control, right lane: patient.