Lethal Multiple Pterygium Syndrome

A rare genetic multiple pterygium syndrome characterized by intrauterine growth retardation, fetal akinesia, multiple joint contractures causing severe arthrogryposis and pterygia (webbing) across multiple joints. Cystic hygroma and/or fetal hydrops are almost invariably present.

Epidemiology

To date, less than 50 fetuses have been reported in 28 families. Of these cases, approximately 60% were male and 40% were female. Half of the families had affected males only, including five with multiple affected males.

Clinical description

Lethal multiple pterygium syndrome (LMPS) is characterized by growth deficiency of prenatal onset, pterygia present in multiple areas (chin to sternum, cervical, axillary, humero-ulnar, crural, popliteal and the ankles) and flexion contractures giving rise to severe arthrogryposis. Subcutaneous edema varies from mildly edematous skin to fetal hydrops with cystic hygroma, lung hypoplasia, and oligo or polyhydramnios. Facial anomalies include hypertelorism, down-slanting palpebral fissures, epicanthic folds, flat nasal root, microretrognathism, microstomia, low-set malformed ears and cleft palate. Other anomalies include a small chest, reduced muscle bulk, cryptorchidism, central nervous system abnormalities (in particular cerebellar hypoplasia, ventricular dilatation and polymicrogyria), hypoplastic dermal ridges and creases, and less frequently a mid-forehead hemangioma, intestinal malrotation, cardiac hypoplasia, diaphragmatic hernia, obstructive uropathy, rocker bottom feet, microcephaly and/or cerebellar and pontine hypoplasia.

Etiology

Causal mutations have been identified in subunits of the acetylcholine receptor encoded by CHRNA1 (2q31.1), CHRND (2q37.1), CHRNG (2q37.1), as well as in the nebulin gene (NEB, 2q23.3), and the ryanodine receptor (RYR1, 19q13.2).

Diagnostic methods

Diagnosis is suspected based on characteristic clinical features and ultrasound findings observed during routine pregnancy examination (for more details see the section on antenatal diagnosis).

Differential diagnosis

Differential diagnoses include other disorders which present with prenatal ultrasound features of reduced or absent fetal movements in association with an abnormal fetal posture and other arthrogrypotic conditions. These may include fetal akinesia deformation sequence (FADS), Bartsocas-Papas syndrome, Escobar variant multiple pterygium syndrome, arthrogryposis multiplex congenita, and maternal myasthenia gravis, as well as trisomy 18, severe neural tube defects, caudal regression sequence and vertebral anomalies, limb body wall complex, fetal neck masses, fetal hypoxia, constriction rings syndrome and fetal constraint.

Antenatal diagnosis

Fetal akinesia may be detected as early as 12 weeks. Prenatal ultrasound findings with LMPS include intrauterine growth retardation, flexion contractures of the limbs, multiple pterygia, cystic hygroma, fetal hydrops, hypoplastic lungs, a cleft palate and other structural abnormalities. Additional findings of hypoplastic skeletal development may help in distinguishing LMPS from other conditions with FADS, and detailed ultrasound scans and fetal MRI may identify a central nervous system abnormality which may be a feature in LMPS or suggest an alternative etiology. Molecular prenatal genetic testing can be undertaken if early scans are inconclusive and the mutation has been identified. LMPS should also be considered in patients with a history of recurrent mid-trimester losses.

Genetic counseling

The inheritance is autosomal recessive. The sibling recurrence risk is 25%. X-linked inheritance has also rarely been reported and is also suggested by the excess of males with LMPS.

Management and treatment

As the condition is lethal, termination of the pregnancy may be proposed.

Prognosis

LMPS is typically fatal during the second or third trimester.