Fetal arthrogryposis multiplex congenita/fetal akinesia deformation sequence (FADS)—Aetiology, diagnosis, and management

Abstract

Arthrogryposis multiplex congenita (AMC) refers to an aetiologically heterogenous condition, which consists of joint contractures affecting two or more joints starting prenatally. The incidence is approximately one in 3000 live births; however, the prenatal incidence is higher, indicating a high intrauterine mortality. Over 320 genes have been implicated showing the genetic heterogeneity of the condition. AMC can be of extrinsic aetiology resulting from intrauterine crowding secondary to congenital structural uterine abnormalities (eg, bicornuate or septate uterus), uterine tumors (eg, fibroid), or multifetal pregnancy or intrinsic/primary/fetal aetiology, due to functional abnormalities in the brain, spinal cord, peripheral nerves, neuromuscular junction, muscles, bones, restrictive dermopathies, tendons and joints. Unlike many of the intrinsic/primary/fetal causes which are difficult to treat, secondary AMC can be treated by physiotherapy with good response. Primary cases may present prenatally with fetal akinesia associated with joint contractures and occasionally brain abnormalities, decreased muscle bulk, polyhydramnios, and nonvertex presentation while the secondary cases usually present with isolated contractures. Complete prenatal and postnatal investigations are needed to identify an underlying aetiology and provide information regarding its prognosis and inheritance, which is critical for the obstetrical care providers and families to optimize the pregnancy management and address future reproductive plans.

Genetic diagnosis and clinical evaluation of severe fetal akinesia syndrome

“…For the definition of AMC or FADS at least two or more joint contractures in different body areas have to be present. 1,2 The phenotype of FADS includes features like intrauterine growth restriction (IUGR), craniofacial anomalies, limb contractures, pulmonary hypoplasia, short umbilical cord, together with pregnancy complications such as polyhydramnios and abnormal intrauterine positioning. This phenotype can occur isolated or associated with additional organ system anomalies.…”

“…Many different alternative nomenclatures have been described in the literature including multiple congenital contractures (MCC), and most commonly arthrogryposis multiplex congenita (AMC). For the definition of AMC or FADS at least two or more joint contractures in different body areas have to be present 1,2 …”

Biallelic c.1263dupC in DOK7 results in fetal akinesia deformation sequence

“…A biallelic variant in DOK7 was reported with lethal FADS in a single family with three affected fetuses (Vogt et al, ). FADS is a clinically and genetically heterogeneous condition with reduced fetal movements, joint contractures, lung hypoplasia, intrauterine growth retardation, and cleft palate (Niles, Blaser, Shannon, & Chitayat, ). Herein, we describe a family with FADS due to biallelic pathogenic variant c.1263dupC in DOK7 which was earlier reported to cause congenital myasthenic syndrome 10.…”

Prenatal delineation of a distinct lethal fetal syndrome caused by a homozygous truncating KIDINS220 variant

“…Over 400 different conditions with arthrogryposis multiplex congenita have been identified and over 320 genes are involved (Hall & Kiefer, 2016; Han et al, 2020); however, the most severe neonatal lethal form is rare and only a minority of affected cases currently obtains a definite genetic diagnosis (Han et al, 2020; Niles, Blaser, Patrick Shannon, & Chitayat, 2019; Todd et al, 2015). We speculate that the AMC phenotype in this fetus occurs due to the loss of brain neurons seen in the mouse embryos and looks more severe than the previously reported KIDINS220 cases based on the early gestational age at the diagnosis of joint contractures and the associated hydrops fetalis.…”