Multiple Pterygium Syndrome, Lethal Type

A number sign (#) is used with this entry because the lethal form of multiple pterygium syndrome (LMPS) is caused by homozygous or compound heterozygous mutation in the CHRNG gene, which encodes the gamma subunit of the acetylcholine receptor (AChR), (100730) on chromosome 2q.

Mutations in this gene can also cause the nonlethal (Escobar) variant of this phenotype (EVMPS; 265000).

Mutations in the CHRNA1 (100690) and CHRND (100720) genes can also result in lethal multiple pterygium syndrome; mutations in these genes can also cause fast- or slow-channel congenital myasthenic syndromes (608930 and 601462, respectively).

Clinical Features

In addition to a lethal multiple pterygium syndrome (Gillin and Pryse-Davies, 1976), Hall (1984) identified 2 other possibly distinct forms: one with spinal fusion and one with congenital bone fusions (van Regemorter et al., 1984). Chen et al. (1984) reported 6 cases. Van Regemorter et al. (1984) documented the lethal multiple pterygium syndrome in 2 spontaneously aborted fetuses from first-cousin parents of Moroccan origin. They had had 3 additional pregnancies that resulted in intrauterine death in the first trimester but information on the concepti was not available. Isaacson et al. (1984) reported a case.

Martin et al. (1986) described lethal multiple pterygium syndrome in 3 sib fetuses. They suggested that antenatal diagnosis is possible in most pregnancies after an index case because of cystic hygroma and hydrops. In the term or near-term infant in which ultrasound does not show cystic hygroma or hydrops, Pena-Shokeir syndrome type I (208150) should be considered; pterygia are a component of that disorder but hygroma and hydrops are not. In brother and sister, Robinson et al. (1987) described a lethal type of multiple pterygium syndrome in which malignant hyperthermia was a major complication. They thought this represented a 'newly recognized disorder.' On the basis of autopsy studies in 4 unrelated fetuses with lethal multiple pterygium syndrome, Moerman et al. (1990) suggested that the disorder combines manifestations of a jugular lymphatic obstruction sequence with those of an early severe fetal akinesia sequence. Generalized amyoplasia appeared to be an important mechanism in the pathogenesis of the fetal akinesia. In 2 of the cases, there was previous birth of a similarly affected fetus.

Clementi et al. (1995) described a family in which 3 fetuses were probably affected, the diagnosis having been missed in the first of these because of misinterpretation of a cystic mass in the neck region, detected by ultrasound at the twentieth gestational week, as a cervical meningocele. The importance of fetal physical examination and supplementary studies to serve as the diagnosis for the sake of appropriate genetic counseling was emphasized.

Meyer-Cohen et al. (1999) raised the question of the existence of an X-linked recessive type of lethal multiple pterygium syndrome (see 312150). They described 4 affected male fetuses in a family with nonconsanguineous parents. A review of the literature since the report by Gillin and Pryse-Davies (1976) uncovered a total of 43 fetuses with lethal multiple pterygium syndrome in 27 families. Of these cases, 24 fetuses were male and 19 were female. Thirteen of the 27 families had affected males only, including 5 with multiple affected males. Their report represented the sixth such family. The only family with reasonably clear X-linked prenatal lethal multiple pterygium syndrome was that reported by Tolmie et al. (1987).

Molecular Genetics

Hoffmann et al. (2006) and Morgan et al. (2006) found mutations in the CHRNG gene (e.g., 100730.0002) causing the lethal form of multiple pterygium syndrome.

Michalk et al. (2008) found mutations in the CHRNA1 (e.g., 100690.0013) and CHRND (e.g., 100720.0005) genes that caused lethal multiple pterygium syndrome.