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

• 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

FETAL AKINESIA DEFORMATION SEQUENCE

ETIOPATHOGENESIS

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

ETIOPATHOGENESIS

INTRAUTERINE CONSTRAINT

• Extrinsic pressure
• Oligohydramnios
• Uterus abnormalities

ANOMALIES ALONG THE MOTOR PATHWAY

• CNS -> PNS -> neuromuscular junction -> muscle

METABOLIC CONNECTIVE TISSUE DISORDERS

• Restrictive dermopathy

MATERNAL ILNESS

• Myotonic dystrophy
• Infections (CMV)
• Maternal antibodies (Myasthenia gravis)

MEDICATION/TERATOGENIC EXPOSURE VASCULAR COMPROMISE

A defintive cause may not always be determinable despite extensive investigation

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

PHENOTYPE

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

Heterogenous genetic background

CHRNA1 CHRNB1 CHRND CHRNG RAPSN DOK7 CNTN1 SYNE1

Genes involved in the motor development An increasing number of genes have been identified but the subsiding molecular defect remains unexplained in most cases

GENETICS

SMN1 ERBB3 GLE1 PIP5K1C UBE1

CASE REPORTS

COIMBRA UNIVERSITY HOSPITAL CENTRE BISSAYA BARRETO MATERNITY

CASE 1

Father: 31 years old, healthy Mother: 30 years old Past medical history:

• I miscarriage(1st trimester)
• II voluntary interruption of pregnancy
• II medical termination of pregnancy (23 weeks)
• 12w 3d Ultasound – Normal
• Chorionic villous sampling – 46, XX

Polimalformed fetuses

• Hydropsy
• Trisomy 18 like phenotype

No autopsy or Karyotyping

CASE 1

22w 4d Ultr ltrasound

• Nonimmune fetal hydrops
• Subcutaneous edema
• Bilateral pleural effusion
• Decreased limbs movement
• Extension of the lower limbs
• Flexion of the upper limbs
• Clenched hands
• Rocker-bottom feet
• Lisossomal disorders – Normal
• Hydrops study – Normal
• CGH Array - Normal

Medical termination of pregnancy 23w 3d

CASE 1 – Autopsy Findings

23w 3d

Limbs Craniofacial features General/Visceral anomalies

• Fetal hydrops
• subcutaneous edema
• nuchal cystic hygroma
• bilateral pleural effusion
• Pulmonary hypoplasia
• Congenital heart defect:

atrial septal defect within the fossa oval, extending to the inferior vena cava

• Sphenoid wings deeper

than usual, less calcified

• Oblique palpebral

fissures

• Slopped forehead
• Wide nasal bridge
• Large mouth
• Macroglossia
• Low-set dysplastic ears



Hands

• flexion of the third finger
• large thumb
• camptodactyly
• 2nd and 3rd finger
• verlap



Rocker-bottom feet and a long hallux

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:
• 1 perinatal death 25 hours after birth
• 1 healthy daughter
• 1 tubal pregnancy

Non-consaguineous couple Both had normal karyotype

Clinical, imagiological and pathological findings

• Congenital Pneumonia
• Autopsy- pulmonar hypoplasia

CASE 2

• Fetal hypomotility
• Polyhydramnios
• Umbilical vein dilatation
• Sugestive of hepatomegaly
• Subcutaneous edema

32 32w w 1d Ultr ltrasound

Amniocentesis

• Lisossomal diseases – Normal
• Spinal muscular atrophy - Normal
• Myotonic distrophy - Normal

Mother is hospitalized for corthicotherapy to induce pulmonary maturation Ultrasound anomalies kept

Medical termination of pregnancy 34w 2d

• Antropometric parameters

above the 50th percentile

• Subcutaneous edema
• 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 – Autopsy Findings

34w 2d

Limbs Craniofacial features General/Visceral anomalies

• Incomplete extension of

inferior limbs (atrogryposis?)

• Forehead and orbital edema
• Hypertelorism
• Abnormal foldind of the ears

CASE 2 Fetal whole exome sequencing - Next Generation Sequencing

• Two heterozygous variants of RYR1 gene

Maternal origin c.9262 G>A (p.Val3088Met) Paternal origin 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

29w w 1d d Ultr trasound

• Decreased fetal movement
• Polyhydramnios
• Hydrops
• Cranial and face edema
• Severe bilateral hydrotorax

CASE 3

Medical termination of pregnancy 29w 3d

• Extension of the inferior limbs, with external rotation
• f on leg and internal rotation of the opposite
• Club foot
• Flexion of the superior limbs with clenched hands and

ulnar deviation

Mother: 33 years old, no relevant past medical history Father: 37 years old, healthy

CASE 3- Autopsy Findings

29w 3d

Limbs General/Visceral anomalies

• Severe lung hypoplasia
• Intracardiac thrombus and on renal vein
• Short neck
• Eosinophilic colitis
• Bone marrow showed predominance of

the eosinophil lineage

• Artrogryposis
• External rotation of inferior right limb

and internal rotation of the left one

• Hands with ulnar deviation and

camptodactyly

CASE 3- Autopsy Findings

Suspected primary trombophilia

• Inherited trombophilias study – no risk factors
• Molecular study – PAI-1 4G/4G
• Lisossomal disorders - Normal
• Smith-Lemli-Opitz syndrome - Normal
• Carbohidrate deficient transferrin - 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

Trisomy 18 Potter syndrome Lethal Larsen Syndrome

DIFERENTIAL DIAGNOSIS

• No pulmonar hypoplasia
• No visceral anomalies
• Not lethal!
• Survival with adequate life quality is

possible with early phyisiotherapy and

• rthopedic care

LETHAL MULTIPLE PTERYGIUM SYNDROME

• Early akinesia and hydrops
• Joint pterigia
• Phenotipical overlap – not a diferent

syndrome?

• In utero letality on 2nd/3rd trimester

ARTROGRYPOSIS MULTIPLEX CONGENITA (AMC)

PROGNOSIS

Depends on the severity of the phenotipic anomalies

• AMC – improvement with AChE inhibitors
• Premature birth
• Born at term with low weight
• 30% are stillborn

Majority of live-born die within the first month

• f life of pulmonary hypoplasia complications

GENETIC COUNSELING AND SURVEILLANCE

Investigation of the fetus with contractures:

• Full pregnancy history (premature membrane

rupture)

• Autopsy (examination of the urinary tract)
• 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