Lethal Multiple Pterygium Syndrome: A South African case series with genomic investigation using whole exome sequencing

Smit, Liani (2020-12)

Thesis (MMed)--Stellenbosch University, 2020.

Thesis

Introduction:Lethal multiple pterygium syndrome (LMPS) is a rare andlethal neuromuscular disorder of the fetus. Cases are characterised by absent fetal movement (fetal akinesia) causing arthrogryposis with pterygia of major joints and inevitable intrauterine lethality. LMPS is a genetically heterogenous single gene disorder, following either autosomal or X-linked recessive patterns of inheritance. Epidemiologic, phenotypic, and genomic LMPS data have not been established in a South African population. Methods:Cases matching the LMPS definition were ascertained retrospectively (2011-2015) and prospectively (2016-2018) from medical genetic and fetal medicine records at Tygerberg Hospital. Comprehensive phenotyping was performed using prenatal ultrasound, clinical, photographic, radiologic and autopsy sources. Genomic investigationusingwhole exome sequencing (WES), was undertaken in an initial trio (affected fetus and unaffected parents) aimed at detecting disease-causing variants in known or novel genes associated with LMPS. Results:Over an 8-year period, 20 women with25 affected fetuses (11 females, 10 males, 4 unknown sex) were identified of predominantly Black South African ancestry (18/20). 20% of women had knownLMPS recurrence with the same non-consanguineous partner. Our data support an estimated LMPS prevalencerate of 1 in 20,000 inour referral area which manages approximately 50,000 deliveries per year. LMPS or non-AbstractIntroduction:Lethal multiple pterygium syndrome (LMPS) is a rare andlethal neuromuscular disorder of the fetus. Cases are characterised by absent fetal movement (fetal akinesia) causing arthrogryposis with pterygia of major joints and inevitable intrauterine lethality. LMPS is a genetically heterogenous single gene disorder, following either autosomal or X-linked recessive patterns of inheritance. Epidemiologic, phenotypic, and genomic LMPS data have not been established in a South African population. Methods:Cases matching the LMPS definition were ascertained retrospectively (2011-2015) and prospectively (2016-2018) from medical genetic and fetal medicine records at Tygerberg Hospital. Comprehensive phenotyping was performed using prenatal ultrasound, clinical, photographic, radiologic and autopsy sources. Genomic investigationusingwhole exome sequencing (WES), was undertaken in an initial trio (affected fetus and unaffected parents) aimed at detecting disease-causing variants in known or novel genes associated with LMPS. Results:Over an 8-year period, 20 women with25 affected fetuses (11 females, 10 males, 4 unknown sex) were identified of predominantly Black South African ancestry (18/20). 20% of women had knownLMPS recurrence with the same non-consanguineous partner. Our data support an estimated LMPS prevalencerate of 1 in 20,000 inour referral area which manages approximately 50,000 deliveries per year. LMPS or non-viability was antenatally recognized in 72% (18/25), with 78% (14/18) of women opting for termination of pregnancy. Half of women (2/4) who continued,developed complications, i.e. preeclampsia and hydrops fetalis precluding vaginal delivery (1/4) andsevere polyhydramnios with acute severe hypertension (1/4). Antenatal non-recognition of non-viability (7/25) occurred outside the Fetal Medicine unit and often resulted in unnecessary Caesarean section (2/7). First trimester sonographyhad a 100% (3/3) detection rate of severe fetal akinesia, i.e. multiple fixed flexion joint deformities, increased nuchal translucency, generalised oedema and reduced or absent fetal movements, but not pterygia. In addition to these findings, 2ndand 3rdtrimester fetal anatomy sonography in 16 pregnancies detected abnormal positioning of the feet (75%), pulmonary hypoplasia (63%), micrognathia (56%), pterygia (50%) and camptodactyly (50%). Fetal hydrops increased from 66% during the 1sttrimester to 80% after 24 weeks. Dysmorphology assessments (22/25) supplemented by photographic phenotyping (7/25), radiologic (6/25) and autopsy (10/25) examinations supportedantenatal findings. Several patterns emerged, includingsimilar facial dysmorphology (5/7), abnormal curvature of the spine (6/6) and evidence for possible cardiac and smooth muscle involvement, i.e. cardiac hypoplasia (2/10) on autopsy,and genitourinary tract dilatation (5/25) on ultrasound.Muscle histology was non-contributory, though immunohistochemistry was unavailable. Initial trio WES did not detect disease-causing variants in known LMPS or fetal akinesia genes but identified ASCC3is a possible gene of interest in LMPS. Conclusion:Our data suggest a 50-fold increased incidence of LMPS in our population compared to previous international estimates and appears more commonamong Black South Africans. Dysmorphic, X-ray and autopsy findings are similar to previous case reports, withadditionalfindings suggesting possible cardiac and smooth muscle involvement in addition to skeletal muscle. The genetic basis of LMPS in our population remains uncertain as no causative mutations were detected on a single trio subjected to WES. While geneticheterogeneity is possible, our case series supports an autosomal recessive pattern of inheritance, with recurrence risk implicationsfor couples. Severe fetal akinesia is detectable from 1sttrimester ultrasound and the presence of hydrops fetalis should prompt review for evidence of fetal akinesia. Early recognition of LMPS and non-viability allows for improved pregnancy management. In ongoing pregnancies there is a need for awareness of increased risk of pregnancy complications and attention to appropriate delivery management. Further genomic investigations may clarify the genetic contribution of LMPS in our population, which could be unique.

Inleiding:Letale meervoudige pterygium sindroom (LMPS) is ‘n raar en dodelike neuromuskulêre kondisie vandie fetus. Gevalleword gekenmerk deur afwesige fetale bewegings (fetale akinesie), met gevolglike veelvuldige kontrakture van die gewrigte (artrogripose) met pterygia enonvermydelike intrauteriene sterfte.Die genetiese oorsake van LMPS is heterogeen en volg‘n outosomaal of X-gekoppeld resessiewe oorerflikheidspatroon. Epidemiologiese, fenotipiese en genomiese data isnie van te vore in die Suid-Afrikaanse populasie vasgestel nie. Metodes:Gevalle wat aan die LMPS definisie voldoen is terugwerkend (2011-2015) en voornemend (2016-2018) identifiseer van mediese genetieseenfetale medisyne rekords by Tygerberg Hospitaal. Omvattende fenotipering is uitgevoer vanuit kliniese,fotografiese,radiologiese en nadoodse ondersoek bronne. ‘n Genomiese ondersoek deur middel van WES is onderneem in ‘n aanvanklike trio (geaffekteerde fetus en beide ongeafekteerde ouers) met die doel om genetiese variante op te spoor in bekende of nuwe gene geassosieerd met LMPS. Resultate:Oor ‘n 8-jaar periode is 20 vroue met 25 geaffekteerde fetusse (11 vroulik, 10 manlik en 4 onbekende geslag)identifiseer van hoofskaalik Swart Suid-Afrikaanse afkoms (18/20). 20% van vroue het ‘n herhaling van LMPSgehad met dieselfde onverwante maat. Onsdata ondersteun ‘n beraamde LMPS prevalensie van 1 in 20,000 in ons verwysingsarea wat ongeveer 50,000 bevallings jaarliks behartig. LMPS of nie-lewensvatbaarheid is voorgeboortelikherken in 72% (18/25), met 78% (14/18) van vroue wat terminasie van swangerskap gekies het. Die helfde (2/4) van vroue wie voortgegaan het met die swangerskap het komplikasies ondervind, naamlik preeklampsie en fetale hydrops wat vaginale verlossing belemmer (1/4) en erge polihidramnios met ernstige akute hipertensie (1/4). Gebrek aan voorgeboorte herkenning van nie-lewensvatbaarheid (7/25) buite die Fetal Medisyne eenheid, het dikwels gelei tot onnodige keisersnitte (2/7).1stetrimestersonografiehet tekens van ernstige fetale akinesie suksesvol in 100% van gevalle identifiseer, naamlik veelvuldige gewrigskontrakture, vergrote NT met algemene edeem en verminderede of afwesige fetale bewegings,maar nie pterygia nie. Bykomend tot hierdie tekens het 2deen3detrimester fetale anatomie sonografie in 16 swangerskappe abnormale positionering van die voete (75%), long hipoplasie (63%), mikrognatie (56%), pterygia (50%) en kamptodaktilie (50%) getoon. Die teenwoordigheid van fetale hidrops het vermeerder van 66% tydens 1stetrimester sonografie tot 80% na 24-weke gestasie.Dismorfologiese(22/25),supplementele fotografiese fenotipering (7/25),radiologiese(6/25)en nadoodse ondersoeke(10/25)het die bevindinge op voorgeboorte sonografie ondersteun. Verskeie patrone het navore gekom, insluitend soortgelyke gesigsdismorfologie (5/7), abnormale kurwatuur van die ruggraat (6/6), asook bewyse van moontlike hart-en gladde-spier betrokkenheid, naamlik hart hipoplasie (2/10) op nadoodse ondersoek en dilatasie van die genitourinêre traktus (5/25) op sonar. Spierhistologie was nie bydraendnie, alhoewel immunohistochemie nie geredelike beskikbaar was nie. Aanvanklike trio WES het geenpatogene variante getoonin bekende LMPS of fetale akinesiegene nie, maar het ASCC3as ‘n moontlike geen van belang in LMPS identifiseer.Samevatting:Ons data dui op ‘n 50-maal verhoogde insidensie van LMPS in ons populasie in vergelyking met vorige internasionale beramings en blyk meer algemeen onder Swart Suid-Afrikaners. Dismorfologiese, X-straal en nadoodse ondersoek bevindingeis soortgelyk aan vorige gevallereekse, met addisionele uitslaewat ook op moontlike hart-en gladde-spier betrokkenheid mag dui. Die genetiese basis van LMPS in ons populasie bly onduidelik in die afwesigheid van enige veroorsakende mutasiesnatrio WES. Terwyl genetiese heterogeniteit moontlik is, ondersteun ons gevallereeks ‘n outosomaal resessiewe patroon van oorwerwing met herhalingsrisiko implikasies vir paartjies. Ernstige fetale akinesie is alreeds waarneembaar tydens 1stetrimester sonografie en die teenwoordigheid van hidrops fetalis noodsaak ‘n deeglike ondersoek vir tekens van fetale akinesie. Vroeë herkenning van LMPS en nie-lewensvatbaarheid, bewerkstellig verbeterde hanteringvan swangerskappe. Bewusmaking rakende verhoogde risiko vir komplikasies en gepaste hantering vanbevallings is noodsaaklik waar swangerskappe voortgaan. Verdere genomiese ondersoeke sal moontlik meer duidelikheid rakende die genetiese bydrae tot LMPS in ons populasiebring.

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