Pena–Shokeir syndrome: current management strategies and palliative care

Figures & data

Table 1 Summary of the genetic causes of Pena–Shokeir phenotype

Anatomical localization	Gene (MIM number)	Gene action	Inheritance pattern	Phenotype	Reference
Brain	TUBB2B (612850)	Beta form of tubulin – major component of microtubules	AD	FADS with MLE	Laquerriere et al (2016)^Citation22
Motor neuron/spinal cord	SMN1 (600354)/SMN2 (601627)	Survival motor neuron protein (SMN1 and 2)	AR	Type 0 SMA	Grotto et al (2016)^Citation23 Devriendt et al (1996)^Citation24
	ERBB3 (190151)	Epidermal growth factor receptor 3	AR	LCCS2	Narkis et al (2004,^Citation25 2007^Citation26)
	GLE1 (603371) – not always lethal	Defective mRNA processing with tissue-specific dysregulation of gene expression causing motor neuron disease	AR	AMC – LCCS1 (253310) and LAAHD (611890) AAHD	Kalampokas et al (2012)^Citation27 Nousiainen et al (2008)^Citation28 Smith et al (2017)^Citation29 Hurt and Silver (2008)^Citation30 Said et al (2017)^Citation31
	PIP5K1C (606102)	Production of phosphatidylinositol- 4,5-biphosphate	AR	LCCS3	Narkis et al (2007)^Citation32
	UBE1 (314370)	Ubiquitin-activating enzyme 1	X-linked	X-L SMA	Ramser et al (2008)^Citation33
Peripheral nerves	EGR2 (129010) MPZ (159440)	Early growth response Myelin protein zero gene		CHN	Warner et al (1998)^Citation34 Warner et al (1996)^Citation35
Neuromuscular junction (embryonal AChR)	CHRNA1 (601592)	AChR α-subunit	AR	LMPS, FADS	Vogt et al (2008)^Citation15 Michalk et al (2008)^Citation14
	CHRNB1 (100710)	AChR β-subunit	AR	LMPS, FADS	Michalk et al (2008)^Citation14
	CHRND (100720)	AChR δ-subunit	AR	LMPS, FADS	Michalk et al (2008)^Citation14
	CHRNG (100730)	AChR γ-subunit	AR	LMPS, AR escobar syndrome, FADS	Morgan et al (2006)^Citation36 vogt et al (2012)^Citation37 Hoffman et al (2006)^Citation38
	RAPSN (601592)	Clustering and anchoring AChR in the postsynaptic membrane of the NMJ	AR	CMS, FADS	Vogt et al (2008)^Citation15 Winters et al (2017)^Citation16
	CNTN1 (600016)	Contactin 1 – NMJ adhesion	AR	FADS, Compton–North congenital myopathy	Compton et al (2008)^Citation39
	DOK7 (610285)	Synaptogenesis through interaction with MUSK	AR	FADS/CMS, familial limb- girdle myasthenia	Vogt et al (2009)^Citation17
	SYNE1 (608441)	Synaptic nuclear envelope protein-1	AR	FADS, myogenic AMC	Attali et al (2009)^Citation40
	ECEL1 (605896)	Endothelin-converting enzyme- like 1	AR	AMC/DA type 5	Dohrn et al (2015)^Citation41
Fetal myostructural proteins	MYH3 (160270)	Myosin heavy chain, embryonic	AD	DA2A, DA2B	Toydemir et al (2006)^Citation42
	MYH8 (160741)	Myosin heavy chain, perinatal	AD	TPS (DA7)	Veugelers et al (2004)^Citation43 Toydemir et al (2006)^Citation44
	MYBPC1 (160794)	Myosin-binding protein C1, skeletal muscle slow type	AD/AR	DA1/LCCS type 4	Gurnett et al (2010)^Citation45
Adult skeletal muscle	NEB (161650)	Sarcomere protein – nebulin	AR	NM/FADS/LMPS	Abdalla et al (2017)^Citation46 Lehtokari et al (2014)^Citation47 Todd et al (2015)^Citation48 Feingold-Zadok et al (2017)^Citation49 Ahmed et al (2018)^Citation50
	RYR1 (180901)	Ryanodine receptor-1	AR, AD	FADS/LMPS/ CCD	McKie et al (2014)^Citation51 Michalk et al (2008)^Citation14 Romero et al (2003)^Citation52
	ACTA1 (102610)	Actin 1, skeletal muscle alpha	AD	NM/FADS	Schroder et al (2004)^Citation53 Ahmed et al (2018)^Citation50
	BICD2 (609797)	Dynein-mediated transport	AD	SMALED	Ahmed et al (2018)^Citation50
	MYOD1 (159970)	MyoD/Myf-5 – myogenic factor	AR	FADS	Watson et al (2016)^Citation54
	DMPK (605377)	Dystrophia myotonica protein kinase	AD	FADS	Winters et al (2017)^Citation16
	MUSK (601296)	Muscle-specific tyrosine kinase	AR	FADS/CMS	Wilbe et al (2015)^Citation20 Tan-Sindhunata et al (2015)^Citation21
	KLHL40 (615340)	Kelch-like 40	AR	NM/FADS	Chen et al (2016)^Citation55
	BIN1 (601248)	Amphiphysin 2	AR	CNM	Nicot et al (2007)^Citation56
	DMPK (160900)	Dystrophia myotonica protein kinase	AD	MD/FADS	Lidang Jensen et al (1995)^Citation57
	FKRP (606596)	Fukutin-related protein	AR	Walker–Warburg syndrome/FADS	Van Reeuwijk et al (2010)^Citation58
	MTM1 (300415)	Myotubularin	X-linked	MTM	Winters et al (2017)^Citation16
	TPM2 (190990)	Tropomyosin 2	AR/AD	MPS escobar variant, DA type 1/2B	Winters et al (2017)^Citation16
	TNNI2 (191042)	Troponin 1 – fast twitch skeletal muscle	AD	DA type 1, DA type 2B	Winters et al (2017)^Citation16
	TNNT3 (600692)	Troponin 3 – fast skeletal muscle	AD	DA type 1, DA type 2B	Winters et al (2017)^Citation16
Chanelopathy	SCN4A (603967)	Sodium channel, voltage-gated type iv, alpha	AR	FADS/CM	Winters et al (2017)^Citation16
	NALCN (611549)	Sodium leak channel, nonselective	AD	CLIFAHDD	Winters et al (2017)^Citation16
Neurometabolic disorders	GBE1 (607839)	Glycogen branching enzyme	AR	GSD iv/FADS	Ravenscroft et al (2013)^Citation59
	PDHA1 (300502)	Pyruvate dehydrogenase alpha-1	X-linked	X-D PDHA/FADS	Winters et al (2017)^Citation16
	DPAGT1 (191350)	Dolichyl-phosphate N-acetylglucosamine phosphotransferase 1	AR	CDG 1J	Ganetzky et al (2015)^Citation60
Immunological causes	FOXP3 (300292)	Forkhead box P3 protein	X-linked	IPEX/FADS	Rae et al (2015)^Citation61
Connective tissue	LMNA (150330)	Lamin A and Lamin C	AR	RD	Smigiel et al (2010)^Citation62
	ZMPSTE24 (606480)	Zinc metalloproteinase involved in the processing of farnesylated proteins	AR	RD	Smigiel et al (2010)^Citation62
Other	FGFR2 (176943)	Fibroblast growth factor receptor 2	AD	Pfeiffer syndrome/LMPS	Baynam et al (2008)^Citation63

Abbreviations: MIM, Mendelian inheritance in Man; AD, autosomal dominant; FADS, fetal akinesia deformation sequence; MLE, microlissencephaly; AR, autosomal recessive; SMA, spinal muscular atrophy; LCCS, lethal congenital contracture syndrome; AMC, arthrogryposis multiplex congenital; LAAHD, lethal arthrogryposis with anterior horn cell disease; AAHD, arthrogryposis with anterior horn cell disease; X-L SMA, X-linked spinal muscular atrophy (301830); CHN, congenital hypomyelination neuropathy; AChR, acetylcholine receptor; LMPS, lethal multiple pterygium syndrome; NMJ, neuromuscular junction; CMS, congenital myasthenic syndrome; DA, distal arthrogryposis; TPS, trismus-pseudocamptodactyly syndrome; NM, nemalin myopathy; CCD, central core disease; SMALED, autosomal dominant spinal muscular atrophy with lower extremity predominance; CNM, centronuclear myopathy; MD, myotonic dystrophy; MTM, myotubular myopathy; MPS, multiple pterygium syndrome; CM, congenital myopathy; CLIFAHDD, congenital contractures of the limbs and face with hypotonia and developmental delay; GSD, glycogen storage disease; X-D PDHA, X-linked dominant pyruvate dehydrogenase E1-alpha deficiency; CDG IJ, Congenital disorder of glycosylation type Ij; IPEX, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; RD, rare disease; FADS, fetal akinesia deformation sequence; AMC, arthrogryposis multiplex congenital; DA, distal arthrogryposis.

Table 2 Differential diagnosis of conditions with markedly decreased intrauterine fetal movements⁶

• Adenylosuccinate lyase deficiency

• Cerebro-oculo-facial syndrome (Pena–Shokeir type 2)

• Congenital myopathies

• Congenital myasthenia gravis

• Fetal akinesia deformation sequence (Pena–Shokeir type 1)

• Fukuyama muscular dystrophy

• Glycosylation type 1A deficiency

• Infantile Pick’s disease

• Lethal Larsen syndrome

• Lethal pterygium syndrome

• Lissencephaly III

• Maternal antibodies to fetal acetylcholine receptor

• Mucopolysaccharidosis III

• Neu–Laxova syndrome

• Progressive encephalopathy, edema, hypsarrhythmia, optic atrophy syndrome

• Phosphofructokinase deficiency (glycogenosis VII)

• Potter syndrome

• Restrictive dermopathy

• Trisomy 18

○ walker–Warburg syndrome

LaquerriereAGonzalesMSaillourYDe novo TUBB2B mutation causes fetal akinesia deformation sequence with microlissencephaly: An unusual presentation of tubulinopathyEur J Med Genet201659424925626732629

 PubMed Web of Science ®Google Scholar

GrottoSCuissetJMMarretSType 0 Spinal Muscular Atrophy: Further Delineation of Prenatal and Postnatal Features in 16 PatientsJ Neuromuscul Dis20163448749527911332

 PubMedGoogle Scholar

DevriendtKLammensMSchollenEClinical and molecular genetic features of congenital spinal muscular atrophyAnn Neurol19964057317388957014

 PubMed Web of Science ®Google Scholar

NarkisGLandauDManorEHomozygosity mapping of lethal congenital contractural syndrome type 2 (LCCS2) to a 6 cM interval on chromosome 12q13Am J Med Genet A2004130A327227615378541

 PubMed Web of Science ®Google Scholar

NarkisGOfirRManorELandauDElbedourKBirkOSLethal congenital contractural syndrome type 2 (LCCS2) is caused by a mutation in ERBB3 (Her3), a modulator of the phosphatidylinositol-3-kinase/ Akt pathwayAm J Hum Genet200781358959517701904

 PubMed Web of Science ®Google Scholar

KalampokasEKalampokasTSofoudisCDeligeoroglouEBotsisDDiagnosing arthrogryposis multiplex congenita: a reviewISRN Obstet Gynecol2012201226491823050160

 PubMedGoogle Scholar

NousiainenHOKestiläMPakkasjärviNMutations in mRNA export mediator GLE1 result in a fetal motoneuron diseaseNat Genet200840215515718204449

 PubMed Web of Science ®Google Scholar

SmithCParboosinghJSBoycottKMExpansion of the GLE1-associated arthrogryposis multiplex congenita clinical spectrumClin Genet201791342643027684565

 PubMed Web of Science ®Google Scholar

HurtJASilverPAmRNA nuclear export and human diseaseDis Model Mech200812–310310819048072

 PubMed Web of Science ®Google Scholar

SaidEChongJXHempelMSurvival beyond the perinatal period expands the phenotypes caused by mutations in GLE1Am J Med Genet A2017173113098310328884921

 PubMed Web of Science ®Google Scholar

NarkisGOfirRLandauDLethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinositol pathwayAm J Hum Genet200781353053917701898

 PubMed Web of Science ®Google Scholar

RamserJAhearnMELenskiCRare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophyAm J Hum Genet200882118819318179898

 PubMed Web of Science ®Google Scholar

WarnerLEManciasPButlerIJMutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathiesNat Genet19981843823849537424

 PubMed Web of Science ®Google Scholar

WarnerLEHilzMJAppelSHClinical phenotypes of different MPZ (P0) mutations may include Charcot-Marie-Tooth type 1B, Dejerine-Sottas, and congenital hypomyelinationNeuron19961734514608816708

 PubMed Web of Science ®Google Scholar

VogtJHarrisonBJSpearmanHMutation analysis of CHRNA1, CHRNB1, CHRND, and RAPSN genes in multiple pterygium syndrome/fetal akinesia patientsAm J Hum Genet200882122222718179903

 PubMed Web of Science ®Google Scholar

MichalkAStrickerSBeckerJAcetylcholine receptor pathway mutations explain various fetal akinesia deformation sequence disordersAm J Hum Genet200882246447618252226

 PubMed Web of Science ®Google Scholar

MorganNVBruetonLACoxPMutations in the embryonal subunit of the acetylcholine receptor (CHRNG) cause lethal and Escobar variants of multiple pterygium syndromeAm J Hum Genet200679239039516826531

 PubMed Web of Science ®Google Scholar

VogtJMorganNVRehalPCHRNG genotype-phenotype correlations in the multiple pterygium syndromesJ Med Genet2012491212622167768

 PubMed Web of Science ®Google Scholar

HoffmannKMullerJSStrickerSEscobar syndrome is a prenatal myasthenia caused by disruption of the acetylcholine receptor fetal gamma subunitAm J Hum Genet200679230331216826520

 PubMed Web of Science ®Google Scholar

WintersLVan HoofEDe CatteLMassive parallel sequencing identifies RAPSN and PDHA1 mutations causing fetal akinesia deformation sequenceEur J Paediatr Neurol201721574575328495245

 PubMed Web of Science ®Google Scholar

ComptonAGAlbrechtDESetoJTMutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathyAm J Hum Genet200883671472419026398

 PubMed Web of Science ®Google Scholar

VogtJMorganNVMartonTGermline mutation in DOK7 associated with fetal akinesia deformation sequenceJ Med Genet200946533834019261599

 PubMed Web of Science ®Google Scholar

AttaliRWarwarNIsraelAMutation of SYNE-1, encoding an essential component of the nuclear lamina, is responsible for autosomal recessive arthrogryposisHum Mol Genet200918183462346919542096

 PubMed Web of Science ®Google Scholar

DohrnNLeVQPetersenAECEL1 mutation causes fetal arthrogryposis multiplex congenitaAm J Med Genet A2015167A473174325708584

 PubMed Web of Science ®Google Scholar

ToydemirRMRutherfordAWhitbyFGMutations in embryonic myosin heavy chain (MYH3) cause Freeman-Sheldon syndrome and Sheldon-Hall syndromeNat Genet200638556156516642020

 PubMed Web of Science ®Google Scholar

VeugelersMBressanMMcDermottDAMutation of perinatal myosin heavy chain associated with a Carney complex variantN Engl J Med2004351546046915282353

 PubMed Web of Science ®Google Scholar

ToydemirRMChenHProudVKTrismus-pseudocamptodactyly syndrome is caused by recurrent mutation of MYH8Am J Med Genet A2006140222387239317041932

 PubMed Web of Science ®Google Scholar

GurnettCADesruisseauDMMcCallKMyosin binding protein C1: a novel gene for autosomal dominant distal arthrogryposis type 1Hum Mol Genet20101971165117320045868

 PubMed Web of Science ®Google Scholar

AbdallaERavenscroftGZayedLBeecroftSJLaingNGLethal multiple pterygium syndrome: A severe phenotype associated with a novel mutation in the nebulin geneNeuromuscul Disord201727653754128336317

 PubMed Web of Science ®Google Scholar

LehtokariVLKiiskiKSandaraduraSAMutation update: the spectra of nebulin variants and associated myopathiesHum Mutat201435121418142625205138

 PubMed Web of Science ®Google Scholar

ToddEJYauKSOngRNext generation sequencing in a large cohort of patients presenting with neuromuscular disease before or at birthOrphanet J Rare Dis20151014826578207

 PubMed Web of Science ®Google Scholar

Feingold-ZadokMChitayatDChongKMutations in the NEB gene cause fetal akinesia/arthrogryposis multiplex congenitaPrenat Diagn201737214415027933661

 PubMed Web of Science ®Google Scholar

AhmedAASkariaPSafinaNPArthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathiesAm J Med Genet A2018176235936729274205

 PubMed Web of Science ®Google Scholar

McKieABAlsaediAVogtJGermline mutations in RYR1 are associated with foetal akinesia deformation sequence/lethal multiple pterygium syndromeActa Neuropathol Commun20142114825476234

 PubMed Web of Science ®Google Scholar

RomeroNBMonnierNViolletLDominant and recessive central core disease associated with RYR1 mutations and fetal akinesiaBrain2003126Pt 112341234912937085

 PubMed Web of Science ®Google Scholar

SchroderJMDurlingHLaingNActin myopathy with nemaline bodies, intranuclear rods, and a heterozygous mutation in ACTA1 (Asp154Asn)Acta Neuropathol2004108325025615221331

 PubMed Web of Science ®Google Scholar

WatsonCMCrinnionLAMurphyHDeficiency of the myogenic factor MyoD causes a perinatally lethal fetal akinesiaJ Med Genet201653426426926733463

 PubMed Web of Science ®Google Scholar

WilbeMEkvallSEureniusKMuSK: a new target for lethal fetal akinesia deformation sequence (FADS)J Med Genet201552319520225612909

 PubMed Web of Science ®Google Scholar

Tan-SindhunataMBMathijssenIBSmitMIdentification of a Dutch founder mutation in MUSK causing fetal akinesia deformation sequenceEur J Hum Genet20152391151115725537362

 PubMed Web of Science ®Google Scholar

ChenTHTianXKuoPLPanHPWongLCJongYJIdentification of KLHL40 mutations by targeted next-generation sequencing facilitated a prenatal diagnosis in a family with three consecutive affected fetuses with fetal akinesia deformation sequencePrenat Diagn201636121135113827762439

 PubMed Web of Science ®Google Scholar

NicotASToussaintAToschVPanHPWongLCJongYJMutations in amphiphysin 2 (BIN1) disrupt interaction with dynamin 2 and cause autosomal recessive centronuclear myopathyNat Genet20073991134113917676042

 PubMed Web of Science ®Google Scholar

Lidang JensenMRixMSchroderHDTeglbjaergPSEbbesenFFetal akinesia-hypokinesia deformation sequence (FADS) in 2 siblings with congenital myotonic dystrophyClin Neuropathol19951421051087606895

 PubMed Web of Science ®Google Scholar

Van ReeuwijkJOlderode-BerendsMJVan den ElzenCA homozygous FKRP start codon mutation is associated with Walker-Warburg syndrome, the severe end of the clinical spectrumClin Genet201078327528120236121

 PubMed Web of Science ®Google Scholar

RavenscroftGThompsonEMToddEJWhole exome sequencing in foetal akinesia expands the genotype-phenotype spectrum of GBE1 glycogen storage disease mutationsNeuromuscul Disord201323216516923218673

 PubMed Web of Science ®Google Scholar

GanetzkyRIzumiKEdmondsonAFetal akinesia deformation sequence due to a congenital disorder of glycosylationAm J Med Genet A2015167A102411241726033833

 PubMed Web of Science ®Google Scholar

RaeWGaoYBunyanDA novel FOXP3 mutation causing fetal akinesia and recurrent male miscarriagesClin Immunol2015161228428526387632

 PubMed Web of Science ®Google Scholar

SmigielRJakubiakAEsteves-VieiraVNovel frameshifting mutations of the ZMPSTE24 gene in two siblings affected with restrictive dermopathy and review of the mutations described in the literatureAm J Med Genet A2010152A244745220101687

 PubMed Web of Science ®Google Scholar

BaynamGSmithNGoldblattJA c.1019A > G mutation in FGFR2, which predicts p.Tyr340Cys, in a lethally malformed fetus with Pfeiffer syndrome and multiple pterygiaAm J Med Genet A2008146A172301230318671283

 PubMed Web of Science ®Google Scholar

HallJGPena-Shokeir phenotype (fetal akinesia deformation sequence) revisitedBirth Defects Res A Clin Mol Teratol200985867769419645055

 PubMed Web of Science ®Google Scholar