FETAL AKINESIA DEFORMATION SEQUENCE PAULA SERRA, RAQUEL PINA, - PowerPoint PPT Presentation

FETAL AKINESIA DEFORMATION SEQUENCE PAULA SERRA, RAQUEL PINA, TERESA CARMINHO, FABIANA RAMOS, EULÁLI A GALHANO Surgical Pathology Department Department of Medical Genetics

FETAL AKINESIA DEFORMATION SEQUENCE • A condition of decreased or absent fetal movements in utero leading to a series of constant, predictable anomalies PENA-SHOKEIR PHENOTYPE

FETAL AKINESIA DEFORMATION SEQUENCE Described similar clinical features but different pathological findings

FETAL AKINESIA DEFORMATION SEQUENCE • 1986, Hall suggested that this did not represent a specific syndrome but rather described a phenotype produced by fetal akinesia, with heterogeneous causes • Incidence 1:12 000 births

ETIOPATHOGENESIS For normal development the fetus needs to be able to move freely from 7 to 8 weeks of gestation onward (Porter, 1995). Any situation that limits the intrauterine space or movement may result in FADS

ETIOPATHOGENESIS INTRAUTERINE CONSTRAINT CONNECTIVE TISSUE DISORDERS ◦ Extrinsic pressure ◦ Restrictive dermopathy ◦ Oligohydramnios ◦ Uterus abnormalities MATERNAL ILNESS ◦ Myotonic dystrophy ◦ Infections (CMV) ANOMALIES ALONG THE MOTOR PATHWAY ◦ Maternal antibodies (Myasthenia gravis) ◦ CNS -> PNS -> neuromuscular junction -> muscle MEDICATION/TERATOGENIC EXPOSURE METABOLIC VASCULAR COMPROMISE A defintive cause may not always be determinable despite extensive investigation

PHENOTYPE INTRAUTERINE GROWTH RESTRICTION JOINT CONTRACTURES PULMONARY HYPOPLASIA CRANIOFACIAL ANOMALIES POLYHYDRAMNIOS SHORT GUT SHORT UMBILICAL CORD

PHENOTYPE NUCHAL CYSTIC HYGROMA SUBCUTANEOUS EDEMA PTERIGIUM CLENCHED HANDS ABSENCE OF THE FLEXION CREASES ON FINGERS AND PALMS

GENETICS Frequently there’s a previous positive family history  Autosomal recessive inheritance • Frequent consaguinity  Autosomal dominant inheritance also described  An X-linked dominant form also exists One-half of the cases are sporadic

CHRNA1 CHRNB1 CHRND CHRNG RAPSN DOK7 CNTN1 SYNE1 Heterogenous genetic background

GENETICS Genes involved in the motor development SMN1 ERBB3 GLE1 PIP5K1C UBE1 An increasing number of genes have been identified but the subsiding molecular defect remains unexplained in most cases

CASE REPORTS BISSAYA BARRETO MATERNITY COIMBRA UNIVERSITY HOSPITAL CENTRE

CASE 1 Father: 31 years old, healthy Mother: 30 years old Past medical history: - I miscarriage(1st trimester) Polimalformed fetuses - II voluntary interruption of pregnancy - Hydropsy - II medical termination of pregnancy (23 weeks) - Trisomy 18 like phenotype No autopsy or Karyotyping • 12w 3d Ultasound – Normal • Chorionic villous sampling – 46, XX

CASE 1 22w 4d Ultr ltrasound  Lisossomal disorders – Normal  Nonimmune fetal hydrops  Hydrops study – Normal  Subcutaneous edema  CGH Array - Normal  Bilateral pleural effusion  Decreased limbs movement  Extension of the lower limbs Medical termination of pregnancy 23w 3d  Flexion of the upper limbs  Clenched hands  Rocker-bottom feet

CASE 1 – Autopsy Findings 23w 3d General/Visceral anomalies Craniofacial features Limbs • Fetal hydrops • Sphenoid wings deeper  Hands than usual, less calcified - flexion of the third finger - subcutaneous edema - large thumb • Oblique palpebral - camptodactyly - nuchal cystic hygroma fissures - 2nd and 3rd finger • Slopped forehead - bilateral pleural effusion overlap • Pulmonary hypoplasia • Wide nasal bridge  Rocker-bottom feet and a • Congenital heart defect: • Large mouth long hallux atrial septal defect within • Macroglossia the fossa oval, extending to the inferior vena cava • Low-set dysplastic ears

CASE 1 Fetal whole exome sequencing - Next Generation Sequencing • Homozygous variant of RAPSN gene c.1029_1045del (p.Glu344Cysfs*127 ) Very low frequency – 0,0036% (ExAc) Not described on literature as pathogenic Originates a truncated protein -> probably pathogenic FURTHER STUDIES - Autoimmune diseases, Hormonal disturbances, Trombophilias

CASE 2 Father: 33 years old, healthy Mother: 33 years old • Past medical history: Clinical, imagiological and pathological findings • - 1 perinatal death 25 hours after birth Congenital Pneumonia • Autopsy- pulmonar hypoplasia - 1 healthy daughter - 1 tubal pregnancy Non-consaguineous couple Both had normal karyotype

CASE 2 Amniocentesis 32w 32 w 1d Ultr ltrasound ◦ Lisossomal diseases – Normal ◦ Spinal muscular atrophy - Normal • Fetal hypomotility ◦ Myotonic distrophy - Normal • Polyhydramnios • Umbilical vein dilatation Mother is hospitalized for corthicotherapy to • Sugestive of hepatomegaly induce pulmonary maturation • Subcutaneous edema Ultrasound anomalies kept Medical termination of pregnancy 34w 2d

34w 2d CASE 2 – Autopsy Findings General/Visceral anomalies Craniofacial features Limbs • Antropometric parameters • Incomplete extension of • Forehead and orbital edema above the 50th percentile inferior limbs (atrogryposis?) • Hypertelorism • Subcutaneous edema • Abnormal foldind of the ears • Severe lung hypoplasia • Straight heart • Intense liver hematopoiesis • Subarachnoid hemorrhage and thin corpus callosum • Hemorrhage of bone marrow, adrenal glands, liver, spleen, kidneys

CASE 2 Fetal whole exome sequencing - Next Generation Sequencing • Two heterozygous variants of RYR1 gene Maternal origin Paternal origin c.9262 G>A (p.Val3088Met) c.13639 G>A (p.Val4547Met ) Variants not described in literature The first one is located on a highly conserved amino acid residue and bioinformatic analysis suggests pathogenicity

CASE 3 Mother: 33 years old, no relevant past medical history Father: 37 years old, healthy 29w w 1d d Ultr trasound • Decreased fetal movement • Extension of the inferior limbs, with external rotation of on leg and internal rotation of the opposite • Polyhydramnios • Club foot • Hydrops • Cranial and face edema • Flexion of the superior limbs with clenched hands and • Severe bilateral hydrotorax ulnar deviation Medical termination of pregnancy 29w 3d

CASE 3- Autopsy Findings 29w 3d General/Visceral anomalies Limbs • Severe lung hypoplasia • Artrogryposis • Intracardiac thrombus and on renal vein • External rotation of inferior right limb and internal rotation of the left one • Short neck • Hands with ulnar deviation and • Eosinophilic colitis camptodactyly • Bone marrow showed predominance of the eosinophil lineage

CASE 3- Autopsy Findings Suspected primary trombophilia • Inherited trombophilias study – no risk factors • Molecular study – PAI-1 4G/4G • Lisossomal disorders - Normal • Carbohidrate deficient transferrin - Normal • Smith-Lemli-Opitz syndrome - Normal • CGH array - Normal • Whole Exome Sequencing – on course ….

HISTOLOGICAL FINDINGS • Generally minor and nonspecific findings • Muscle biopsies may show disuse atrophy, rarely with fatty or fibrous replacement.

DIFFERENTIAL DIAGNOSIS Potter syndrome Trisomy 18 Lethal Larsen Syndrome

DIFERENTIAL DIAGNOSIS ARTROGRYPOSIS MULTIPLEX CONGENITA LETHAL MULTIPLE PTERYGIUM SYNDROME (AMC) - No pulmonar hypoplasia - Early akinesia and hydrops - No visceral anomalies - Joint pterigia - Not lethal! - Phenotipical overlap – not a diferent syndrome? - Survival with adequate life quality is possible with early phyisiotherapy and - In utero letality on 2nd/3rd trimester orthopedic care

PROGNOSIS Depends on the severity of the phenotipic anomalies ◦ AMC – improvement with AChE inhibitors - Premature birth Majority of live-born die within the first month - Born at term with low weight of life of pulmonary hypoplasia complications - 30% are stillborn

GENETIC COUNSELING AND SURVEILLANCE • Parents can be counseled along the lines of autosomal recessive inheritance • Prenatal US diagnosis - anomalies detectable as early as 12 weeks, but can vary until the 3rd trimester Investigation of the fetus with contractures: • Full pregnancy history (premature membrane rupture) • Autopsy (examination of the urinary tract)