DDD Study

Saskin, Avi

Tischkowitz, Marc

English

Apollo (Cambridge)

  1 	Jejunal	atresia,	periodic	fevers	and	psoriatic	arthropathy	in	Baraitser	Winter	malformation	syndrome		Avi	Saskin1,	DDD	Study2,	Marc	Tischkowitz3		1.	Department	of	Medical	Genetics,	McGill	University,	Montreal,	Quebec,	Canada	2.	Wellcome	Trust	Sanger	Institute,	Hinxton,	Cambridge,	UK	3.	Department	of	Medical	Genetics,	University	of	Cambridge,	Cambridge,	UK									Corresponding	author:	Dr.	Marc	Tischkowitz	University	Reader	and	Honorary	Consultant	in	the	Department	of	Medical	Genetics	at	Cambridge	Department	of	Medical	Genetics,	Box	134,	Level	6,	Addenbrooke’s	Treatment	Centre,	Addenbrooke’s	Hospital,	Hills	Rd.,	Cambridge	CB2	0QQ,	United	Kingdom	mdt33@cam.ac.uk.													Running	head:	Jejunal	atresia	in	Baraister	Winter	syndrome			Sources	of	support:	Health	Innovation	Challenge	Fund		Key	Words:	Jejunal	atresia,	Periodic	fevers,	Psoriatic	arthropathy,	Baraitser	Winter	malformation	syndrome,	ACTB			  2 	Key	features	Baraitser	Winter	malformation	syndrome	ACTB	Jejunal	atresia	Recurrent	fevers	Psoriatic	arthropathy		Introduction		Baraitser	Winter	malformation	syndrome	(BWMS,	OMIM	243310)	is	an	autosomal	dominant	multi	system	disorder	characterized	by	typical	craniofacial	features,	intellectual	disability,	brain	malformation,	iris	or	retinal	coloboma,	sensorineural	deafness,	and	muscle	wasting	resulting	in	a	typical	stance	with	kyphosis,	anteverted	shoulders,	and	flexed	flexion	deformities	of	elbows	and	knees(Verloes	et	al.,	2015).	BWMS	is	caused	by	mutations	in	the	cytoplasmic	actin	genes	ACTB	and	ACTG1	(Rivière	et	al.,	2012).	To	date,	the	association	of	BWMS	with	jejunal	atresia,	recurrent	fevers	or	psoriatic	arthritis	has	not	been	reported.	Here,	we	describe	a	22	year	old	male	presenting	at	birth	with	jejunal	atresia,	recurrent	fevers,	and	psoriatic	arthritis	with	typical	dysmorphic,	intellectual,	joint	and	auditory	features	of	BWMS	found	to	have	a	novel	heterozygous	pathogenic	ACTB	missense	variant	on	whole	exome	sequencing	(WES).		Clinical	Summary		Our	patient,	now	22	years	old,	initially	presented	at	birth	with	multiple	jejunal	atresias	requiring	a	significant	small	bowel	resection	with	subsequent	short	bowel	syndrome	and	failure	to	thrive	requiring	on-going	gastrostomy	and	enteral	feeding,	further	complicated	by	recurrent	bouts	of	gastrointestinal	bleeding.	He	was	the	result	of	a	natural	conception	with	the	pregnancy	significant	for	maternal	abdominal	pain,	followed	closely	with	nine	normal	prenatal	ultrasounds.	It	was	otherwise	unremarkable.	The	parents	were	of	English,	Swedish	and	German	descent	with	his	mother	and	father	having	two	and	one	unaffected	offspring	with	different	partners	respectively.	Review	of	family	history	was	non-contributory.		At	3	years	of	age,	he	was	noted	to	have	sensorineural	hearing	loss,	requiring	bilateral	hearing	aids,	thought	at	the	time	to	be	related	to	aminoglycoside	exposure.	The	following	year,	he	experienced	an	isolated	seizure	attributed	to	an	electrolyte	imbalance	secondary	to	his	short	bowel	syndrome	treated	with	steroids.	After	weaning	off	steroids,	he	began	to	develop	recurrent	fevers	with	variable	frequency	and	duration.	These	fevers	occurred	without	an	identifiable	trigger,	could	last	up	to	5	days,	can	be	associated	with	erythematous	macules,	and	are	still	ongoing.	Around	the	age	of	17,	he	then	developed	psoriatic	arthritis	treated	with	immunotherapy	and	weekly	methotrexate.	Recently,	beginning	at	the	age	of	21	years,	he	developed	a	predominantly	upper,	left	sided	peripheral	neuropathy	confirmed	on	electromyogram,	with	significant	muscle	wasting.	The	degree	of	muscle	wasting	has	begun	to	impact	his	ability	to	perform	his	activities	of	daily	living	(ADL).		  3 In	terms	of	intellectual	development,	our	patient	had	a	global	developmental	delay	requiring	a	specialized	school,	physio	and	occupational	therapy.	He	is	currently	regarded	as	having	the	mental	abilities	in	the	range	of	a	6-7	year	old.	He	is	described	as	naive	and	innocent,	requiring	assistance	with	all	instrumental	activities	of	daily	living	(IADL)	as	well	as	some	ADLs.			On	physical	examination,	his	growth	parameters	were	under	the	3rd	percentile	for	height	and	weight	with	a	head	circumference	at	the	90th	percentile.	His	facial	appearance	displayed	typical	features	of	BWMS	with	a	prominent	brow,	arched	eyebrows,	hypertelorism,	ptosis,	long	downslanting	palpebral	fissures,	broad	nose	with	large	tip	and	prominent	root,	and	low	set	ears	(Figure	1a).	His	posture,	characteristic	of	BWMS,	was	defined	by	fixed	flexion	deformities	of	the	elbows	and	knees,	and	anteverted	shoulders	(1b).	Additionally,	on	musculoskeletal	examination,	significant	muscular	atrophy	was	evident	in	his	right	hand,	with	limited	strength	and	atrophic	posturing.	Skin	examination	revealed	global	follicular	keratinous	plugging	sparing	the	facial	region.				Investigations		Prior	to	WES	he	had	a	number	of	genetic	investigations	including	karyotype,	microarray,	a	recurrent	fevers	panel	consisting	of	MEFV,	MVK,	NLRP3,	NLRP12	and	TNFRSF1A,	alpha-galactosidase	enzymatic	activity,	GJB2	sequencing,	and	GJB6	deletions	analysis.	Research-based	WES	through	the	Deciphering	Developmental	Disorders	study	(DECIPHER	id	273880)		subsequently	identified	a	heterozygous	pathogenic	ACTB	variant,	namely	c.434C>G	(p.Ser145Cys)	which	was	confirmed	on	clinical	sequencing.	Testing	of	parental	samples	revealed	this	change	to	be	de	novo.		Discussion		Although	rare,	BWMS	has	been	well	characterized	in	the	medical	literature.	The	largest	case	study	by	Verloes	et	al	included	42	molecularly	confirmed	BWMS	cases	with	the	majority	of	these	patients	(33/42)	having	pathogenic	ACTB	pathogenic	missense		variants	(Verloes	et	al.,	2015).	However,	to	date	there	have	been	no	reported	BWMS	patients	affected	with	jejunal	atresia,	recurrent	fevers	or	psoriatic	arthritis.				Jejunal	atresia,	a	complex	surgical	condition,	has	been	found	in	retrospective	studies	to	have	a	high	rate	of	associated	anomalies	in	the	range	of	19-52%	(Best		et	al.,	2012;	Burjonrappa	et	al.,	2011),	the	majority	being	structural	cardiac	defects.	However,	these	studies	have	no	postnatal	data	available	and	full	dysmorphology	work-ups	were	not	completed.	Therefore,	this	value	is	likely	an	underestimate	of	the	true	incidence	of	associated	problems,	including	intellectual	deficiency.	Moreover,	subtle	dysmorphic	features	that	may	not	have	been	evident	at	birth,	such	as	in	our	case,	may	only	come	to	light	over	time.	It	is	therefore	possible	that	a	higher	proportion	of	atresia	cases	have	multisystem	involvement	and	likely	a	genetic	aetiology.	In	our	case,	WES	did	not	identify	other	genetic	causes	that	may	explain	the	jejunal	atresia.	ACTB	is	widely	expressed	in	jejunal	tissue,	with	some	studies	of	the	jejunum	using	ACTB	expression	levels	for	normalisation	of	other	mRNA	levels	or	as	a	control	(Fernández-Blanco	et	al.,	2015	).	It	is	therefore	plausible	that	pathogenic	ACTB	variants	could	have	an	effect	on	intestinal	development.	  4 	With	a	prevalence	of	0.7	per	10,000	births,	jejunal	atresia	is	a	much	rarer	anomaly	than	recurrent	fevers	or	psoriatic	arthritis.	These	two	conditions,	are	not	uncommon,	and	typically	result	from	immunological	dysfunction	and	activation.		Data	from	Riviere	et	al.	indicated	that	mutations	associated	with	BWMS	resulted	in	increased	F-actin	content	and	altered	F-actin	dynamics	in	lymphoblastoid	cell	lines	(Riviere	et	al.	2012).	These	effects	were	predicted	to	impact	cell	morphology,	motility,	and	other	actin-related	functions	in	these	lymphoblast	cells.	Additionally,	multiple	cell	lines	were	investigated	from	a	patient	with	immunological	and	intellectual	dysfunction	found	to	harbour	a	pathogenic	ACTB	variant	(Nunoi	et	al,.	1999).		These	cell	lines	had	altered	immunological	functions	such	as	chemotaxis	that	was	directly	linked	to	actin	function,	and	also	disruption	of	non-actin	related	function	such	as	superoxide	generating	ability.	In	view	of	the	abundance	of	β-actin	in	leukocytes,	it	is	plausible	that	immunological	function	could	be	disrupted	in	BWMS	and	may	have	led	to	or	contributed	to	our	patient’s	psoriatic	arthritis	and	recurrent	fevers.			Conclusion	We	report	the	first	case	of	jejunal	atresia	in	BWMS.	Further	case	reports	will	be	required	to	confirm	the	association	of	BWMS	with	jejunal	atresia	and	immunological	dysfunction.	However,	based	on	the	pathophysiology	cited	above,	the	negative	genetic	testing	prior	to	WES	and	the	lack	of	additional	pathogenic	variants	found	on	WES,	it	is	a	reasonable	possibility	that	the	ACTB	variant	was	causal	or	at	least	contributory	to	our	patient's	phenotype.		Acknowledgements	The	DDD	study	presents	independent	research	commissioned	by	the	Health	Innovation	Challenge	Fund	[grant	number	HICF-1009-003],	a	parallel	funding	partnership	between	the	Wellcome	Trust	and	the	Department	of	Health,	and	the	Wellcome	Trust	Sanger	Institute	[grant	number	WT098051].	The	views	expressed	in	this	publication	are	those	of	the	author(s)	and	not	necessarily	those	of	the	Wellcome	Trust	or	the	Department	of	Health.	The	study	has	UK	Research	Ethics	Committee	approval	(10/H0305/83,	granted	by	the	Cambridge	South	REC,	and	GEN/284/12	granted	by	the	Republic	of	Ireland	REC).	The	research	team	acknowledges	the	support	of	the	National	Institute	for	Health	Research,	through	the	Comprehensive	Clinical	Research	Network.		Conflicts	of	interest	There	are	no	conflicts	of	interest.		Consent		Consent	for	publication	of	clinical	photos	was	given.		References		Best	KE,	Tennant	PW,	Addor	MC,	Bianchi	F,	Boyd	P,	Calzolari	E,	et	al	(2012).	Epidemiology	of	small	intestinal	atresia	in	Europe:	a	register-based	study.	Arch	Dis	Child	Fetal	Neonatal	Ed,	pp.fetalneonatal-2011.	  5 	Burjonrappa	S,	Crete	E,	Bouchard	S	(2011).	Comparative	outcomes	in	intestinal	atresia:	a	clinical	outcome	and	pathophysiology	analysis.	Pediatr	Surg	Int	27(4),	pp.437-442.		Fernández-Blanco	JA,	Estévez	J,	Shea-Donohue	T,	Martínez	V,	Vergara	P	(2015).	Changes	in	epithelial	barrier	function	in	response	to	parasitic	infection:	implications	for	IBD	pathogenesis.	J	Crohns	Colitis,	9(6),	pp.463-476.		Nunoi	H,	Yamazaki	T,	Tsuchiya	H,	Kato	S,	Malech	HL,	Matsuda	I,	Kanegasaki	S	(1999).	A	heterozygous	mutation	of	β-actin	associated	with	neutrophil	dysfunction	and	recurrent	infection.	PNAS	96(15),	pp.8693-8698.		Rivière	JB,	Van	Bon	BW,	Hoischen	A,	Kholmanskikh	SS,	O'Roak	BJ,	Gilissen	C,	et	al	(2012).	De	novo	mutations	in	the	actin	genes	ACTB	and	ACTG1	cause	Baraitser-Winter	syndrome.		Nat	Genet	44(4),	pp.440-444.		Verloes	A,	Di	Donato	N,	Masliah-Planchon	J,	Jongmans	M,	Abdul-Raman	OA,	Albrecht	B,	et	al	(2015).	Baraitser–Winter	cerebrofrontofacial	syndrome:	delineation	of	the	spectrum	in	42	cases.	Eur	J	Hum	Genet,	23(3),	pp.292-301.	 Figures: 1a     1b    Figure 1. Features of BWMS include (a) prominent brow, arched eyebrows, hypertelorism, ptosis, long downslanting palpebral fissures, broad nose with large tip and prominent root, low set ears  (b) fixed flexion deformities of the elbows and knees, and anteverted shoulders   6     

Jejunal atresia, periodic fevers and psoriatic arthropathy in Baraitser-Winter malformation syndrome.

https://www.repository.cam.ac.uk/bitstream/1810/269807/1/Saskin%20DDD%20Tischkowitz%20BWMS%2009JUN17%20-%20DDD%20approved.pdf

Jejunal atresia, periodic fevers and psoriatic arthropathy in Baraitser-Winter malformation syndrome.

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