At the time of writing, the proband (P2) was 41 years old. P2 was born prematurely at 35 weeks, with a low birth weight (2 kg and 25th centile) and was found to have bilateral talipes equinovarus, managed conservatively. P2 was hypermobile as a child with stretchy skin and had a left shoulder dislocation at the age of 1 year. P2 bruised easily and severely, including occasional haematomas which resolved spontaneously and required no drainage. P2's skin is not particularly fragile. P2 has had two pregnancies with vaginal deliveries, where she sustained third-degree tears (obstetric anal sphincter injury), although these healed well. In the late twenties, P2 began to develop gradually worsening lumbar and hip pain, and fatigue with poor-quality sleep. Slow growing hair and generalised thinning of the hair on the scalp were also observed in P2's 20s but were not treated. P2 has recently been diagnosed with high blood pressure, underactive thyroid, and pre-diabetes and has been prescribed clopidogrel, following a transient ischaemic attack. This was diagnosed following an episode of unilateral visual loss in the right eye, with no identified abnormalities on the echocardiogram or ultrasound of the neck. Investigative cardiac rhythm monitoring identified a short period of atrial flutter. An MRI of the head detected a small, old left temporal lacunar infarct, with no evidence of acute infarction. P2 is known to have osteopenia with reduced bone mineral density, along with some sites of osteoarthritis on further imaging of the joints.
On examination at age 34, (see Figure 3, patient's consent has been gained for the use of all clinical photographs), P2 was observed to have no skeletal abnormalities. Earlobes were notched bilaterally. P2 had bilateral pes planus, with prominent piezogenic papules over both heels. The swas hyperextensible with thinning over the chest and papyraceous scarring over the right knee. Multiple subcutaneous spheroids were observed. Follicular keratosis of the skin of the neck and axillae was also observed. On examination, P2 had a single papyraceous scar on the knee, thin skin, and hair thinning over the scalp. There was generalised hypermobility (Beighton score 9/9) plus distal hypermobility of the small joints. P2's hair was observed to be generally thin on the scalp; however, body hair was retained.
Genetic testing at the age of 36 for COL1A1, COL3A1, COL5A1, and COL5A2 including MLPA showed no abnormalities. Transmission electron microscopy of skin biopsy taken from the inner, upper arm showed clumps of collagen fibres with large collagen flowers in the papillary dermis, with normal elastic fibres (see Figure 4). At the age of 38, P2 consented to participate in the 100K project; however, sequencing from the proband's sample unfortunately failed. As such, sequencing of the United Kingdom EDS next-generation sequencing gene panel was arranged, which included ADAMTS2, AEBP1, ALDH18A1, ATP6V0A2, ATP6V1A, ATP7A, B3GALT6, B4GALT7, BGN, C1R, C1S, CBS, CHST14, COL12A1, COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, COL6A1, COL6A2, COL6A3, DSE, EFEMP2, ELN, FBLN5, FBN1, FBN2, FKBP14, GORAB, LOX, LTBP4, PLOD1, PRDM5, PYCR1, RIN2, ROBO3, SKI, SLC39A13, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1, TGFBR2, TNXB, and ZNF469. Recessive variants were identified in AEBP1 (NM_001129.4) c.1012G>T; p. (Glu338*) (PM2, PVS1, and PM3_sup) and c.1930C>T, p. (Arg644*) (PM2, PVS1, and PM3_sup), classified as ACMG class 5.