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Fetal Akinesia - CHRNG, CHRNA1, CHRNB1, CHRND, RAPSN, DOK7

Pena-Shokeir phenotype. Fetal Akinesia Deformation Sequence (FADS); Arthrogryposis multiplex congenita (AMC); Multiple Pterygium Syndrome (MPS); Escobar Syndrome

Clinical Features

Primary restricted intrauterine movement can lead to a special fetal phenotype (Fetal Akinesia Sequence) that can be fatal in extreme cases. This phenotype is characterized by

• Polyhydramnios
• Intrauterin growth retardation
• Pulmonary hypoplasia
• Hydrops
• Flexion contractures

Less severe postnatal phenotypes come in the form of an Arthrogryposis Multiplex Congenita (AMC) with multiple flexion contractures.

Additional abnormalities that may indicate restricted intrauterine mobility are a short umbilical cord or a lack of folds in the fingers and palms. Polyhydramnios is often a sign of fetal dysphagia. Joint pterygium may be an early sign of restricted prenatal mobility in the first trimester and is the result of subcutaneous acroedemas, which are also the cause of the pulmonary hypoplasia and hydrops. Together, these symptoms indicate a lethal or non-lethal form of multiple pterygium or Escobar Syndrome. Dimples also indicate early joint anchorage.

Secondary restricted prenatal mobility, e.g. intrauterine constriction, shows a combination of oligohydramnios, asymmetrical contractures, and breech birth.

The causes of fetal constriction can vary and may be genetic or exogenous. One example of a non-genetic cause is a maternal antibody that works against fetal expression of the gamma-subunit of AChR.

Genetic causes range from central neurological problems to disorders of the motor anterior horn cells, peripheral nerves, and neuromuscular synapses as well as to myopathies and skeletal dysplasia. Many hereditary forms follow an autosomal recessive pattern of inheritance; however, some autosomal dominant and X-linked patterns of inheritance have also been described. Information concerning the prevalence of particular genetic mutations is insufficient at this time.

Important is an exact characterization of the clinical phenotype with respect to the accompanying deformities (e.g., cleft palate, gastroschisis, skeletal abnormalities), muscle hypotonia, or respiratory insufficiency, as well as a detailed family anamnesis (consanguinity, Sudden Infant Death Syndrome, accumulated miscarriages) and, if possible, additional testing of CK-levels, electrophysiology, or even a muscle biopsy. In cases of fetal death or induced abortion, an autopsy should be performed and should include a detailed neuropathological exam, asservation of sample material for DNA analysis, and a muscle biopsy. Conventional chromosome analysis and molecular genetic testing for spinal muscle atrophy (SMA) belong to the spectrum of basic testing.

Genetic Information

The most important molecular genetic diagnostics for this disease involve testing for autosomal recessive mutations in the AChR subunit genes (CHRNA1, CHRNB1, CHRND) and other, synapse-specific genes (RAPSN, DOK7). While more benign missense mutations or compound heterozygous nonsense / missense mutations in these genes lead to the phenotype of congenital myasthenia (CMS), functionally serious missense or nonsense mutations may result in fetal hypokinesia or lethal akinesia (with or without pterygium).

Both the lethal and non-lethal forms of Escobar Syndrome have been attributed to mutations in the CHRNG gene, which codes for the fetal expression of the gamma-subunit of AChR into the 33^rd week of gestation.

Prevalence

Arthrogryposis: 1: 3,000

Diagnostic