Recurrent missense mutation of GDF5 (p.R438L) causes proximal symphalangism in a British family

Table 1 Clinical characteristics of the affected member of the reported family

Affected member (current age)	Hand abnormalities	Tarsal coalition	Conductive hearing loss	Other	Orthopaedic treatment required
Patient 1: Mother (40)	Brachydactyly, no symphalangism	Bilateral: Talonavicular coalition, calcaneocuboid coalition, middle and lateral cuneiform coalition	No	Pituitary adenoma – prolactinoma, platelet storage pool disorder	Yes for painful fixed valgus hindfoot, had targeted injections, developed subtalar osteoarthritis, underwent subtalar fusion
Patient 2: Son (18)	Symphalangism, bilateral little fingers proximal interphalangeal joints fusion1	Bilateral: Calcaneocuboid fusion, 3rd metatarsal - lateral cuneiform, Right talonavicular coalition	No		Orthotics only
Patient 3: Son (15)	Brachydactyly, no symphalangism	Bilateral: Calcaneocuboid coalition, and medial cuneiform to third metatarsal coalition	No	Developmental delay, asthma, under investigation for Marfans	Orthotics only
Patient 4: Daughter (11)	Symphalangism, bilateral little fingers proximal interphalangeal joints fusion1	Bilateral: Calcaneocuboid and talonavicular coalition, and medial cuneiform to third metatarsal coalition	No	Developmental delay, asthma, mild platelet dysfunction	Orthotics only

¹For the symphalangism, bilateral little fingers proximal interphalangeal joints fusion of patients 2 and 4, please see the Figure 2.

Table 2 Identified mutations of GDF5 in relation to proximal symphalangism and multiple synostoses syndrome 2

Ref.	Syndrome	Mutation identified	Effect on codon
Wang et al[6]	SYM1	1471 G - A	Glutaminic acid to lysine (E491K)
Yang et al[7]	SYM1	1118 T - G	Leukine to arginine (L373R)
Seemann et al[4]	SYM1	1632 G - T	Arginine to leucine (R438L)
Dawson et al[5]	SYNS2	1313 G - T	Arginine to leucine (R438L)

SYM1: Proximal symphalangism; SYNS2: Multiple synostoses syndrome 2.