Multiple Pterygium Syndrome, Escobar Variant

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

Mutations in this gene can also cause the lethal variant of this phenotype (LMPS; 253290).

Description

Multiple pterygium syndromes comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (Morgan et al., 2006). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal (253290) and nonlethal (Escobar) types.

Clinical Features

Webbing of the neck, antecubital fossae, and popliteal fossae with sternal deformity and male hypogonadism may behave sometimes as a dominant, but there clearly appears to be a recessive pterygium syndrome. Norum et al. (1969) described a family in which each of 2 cousin sibships contained 2 cases. Of the four, 3 were male and 1 female. Curious 'dents,' cutaneous depressions, were present on the back of the elbows and front of the knees. Gorlin (1974) suggested that the sibs reported by Matolcsy (1936) had this disorder. Matolcsy (1936) described a brother and sister with severe webbing of the neck, axillae, popliteal fossae, and fingers. The boy, aged 13, had cryptorchidism. The sibs reported by Srivastava (1968) as examples of arthrogryposis multiplex congenita appear to have had this disorder. Scott (1969) described an early case. Chen et al. (1980) described 4 affected sibs in a consanguineous Nicaraguan family. Clinical features included short stature; pterygia of the neck, axilla, and antecubital, popliteal, digital, and intercrural areas; multiple joint contractures with crouched stance and cleft palate. Males had small penis and scrotum and cryptorchidism; females had aplasia of the labia majora and small clitoris. Skeletal anomalies included fusion of cervical vertebrae, scoliosis, flexion contraction of fingers, and 'rocker-bottom' feet with vertical talus. Stoll et al. (1980) reported 2 affected sisters of unrelated parents. Lindahl (1981) described a family in which the affected members had dimples at the knees and elsewhere.

In their study of over 350 infants with arthrogryposis, Hall et al. (1982) recognized 11 cases of limb pterygia and congenital contractures. Seven had the autosomal recessive multiple pterygium syndrome: 3 of the 7 were sibs and a fourth was born of consanguineous parents. Three sibs had a lethal multiple pterygium syndrome (see 253290). Two were monozygotic twins. Unusual facies, cleft palate, bilateral pulmonary hypoplasia, small heart, absence of the appendix, and attenuation of the ascending and transverse colon were associated features. Cervical vertebral fusion, loosely labeled Klippel-Feil syndrome (118100), occurs in this disorder. This syndrome, especially in milder cases, may be confused with Noonan syndrome (163950). It is distinct from the popliteal pterygium syndrome (119500, 263650). In a study of the prune belly syndrome (100100), Welling et al. (1975) described what they considered a distinct syndrome in 2 brothers. The features were defects in the abdominal muscles and contractures of the joints without renal anomalies that usually occur with the prune belly syndrome. On restudy, Hempelmann (1979) and Lenz (1985) concluded that the condition is the multiple pterygium syndrome. Lenz (1985) described axillary and neck pterygia, cryptorchidism, fused cervical vertebrae, and camptodactyly. There was general muscular hypoplasia but no conspicuous abdominal muscle defect.

Thompson et al. (1987) presented 11 new cases to show the evolution of the full phenotype from birth and to confirm autosomal recessive inheritance. Morbidity secondary to respiratory impairment and the occurrence of conductive deafness were emphasized. Several of the patients had consanguineous parents and multiple cases in families were reported. Fryns et al. (1988) described longitudinal follow-up data on 2 brothers with multiple pterygium syndrome. Ramer et al. (1988) reviewed the literature and described the longitudinal clinical course of 2 affected sisters. On the basis of the review of Escobar et al. (1978), the eponymic designation Escobar syndrome was proposed by Smith (1982).

In a 15-year-old patient with sporadic multiple pterygium syndrome, presumably the autosomal recessive form, McKusick (1992) observed dilated root of the aorta and moderately severe aortic regurgitation present from birth. In a man with multiple pterygium syndrome who had a similarly affected brother and sister, Hennekam (1993) described a peculiarly shaped tongue which he proposed to name lingua cochlearis (cochlea meaning spoon). The shape of the tongue at protrusion provided clues for an abnormal origin of insertion of the muscles of the tongue. Teebi and Daoud (1990) pointed to a relatively high frequency in Kuwait. In a Hispanic Puerto Rican family, Ramer et al. (1991) described the multiple pterygium syndrome in 3 sibs, including monozygotic twins. In one twin, some findings overlapped with those of the lethal type of pterygium syndrome (253290). The pterygia progressed as the affected individuals aged.

Spranger et al. (1995) reported the cases of 2 sisters with autosomal recessive multiple pterygium syndrome, type Escobar, who showed in addition to multiple pterygia severe contractures, short stature, and minor facial and external genital anomalies. A striking feature was severe muscular atrophy.

Rajab et al. (2005) described 6 Omani children from 2 consanguineous families with a multiple congenital anomaly syndrome showing a high degree of phenotypic overlap with Escobar syndrome but displaying overlap with Freeman-Sheldon syndrome (193700) as well. Affected individuals manifested arthrogryposis multiplex congenita, typical facial appearance, ophthalmologic anomalies, atrophic calf muscles, and interdigital, neck, and axillary pterygia. In addition, the patients presented distinctive features, including furrowed tongue and enlarged corneal nerves, that had not previously been described in association with distal arthrogryposis syndromes. Linkage to 2 known arthrogryposis loci, TPM2 (190990) on 9p13 and TNNI2 (191043) and TNNT3 (600692) on 11p15, was excluded.

Shalev et al. (2005) reported a large multiply consanguineous Arab family in which 9 members had some of the typical features of Escobar syndrome, including pterygium of the neck and occasionally of the antecubital fossa, associated with joint contractures and mild camptodactyly, ptosis, downslanting palpebral fissures, and reduced facial movements. Affected members were unusual in that they lacked pterygia in the lower body, and 8 of 9 had an abnormally widened umbilical area with an umbilical hernia and apparent hypoplasia of the periumbilical skin.

Hoffmann et al. (2006) noted that the first diagnostic sign is that of reduced fetal movement detected by ultrasound or reported by mothers. At birth, the children come to medical attention because of variable joint contractures, multiple pterygia, and facial dysmorphism with long face, high-arched palate, small mouth, and retrognathism. Respiratory distress is a frequent life-threatening complication. Later in life, patients frequently are affected by reduced muscular mass but do not show myasthenic symptoms and have normal electromyelogram (EMG), except for unspecific indication of chronic myopathy.

Prontera et al. (2006) reported a 3-year-old girl with classical clinical features of multiple pterygium syndrome. Careful clinical examination of the father showed subtle minor signs of the disorder, including difficulty in opening the mouth widely, scoliosis, pectus excavatum, slight cutaneous syndactyly, malformed carpal bones, and an altered metacarpal-phalangeal pattern. The authors suggested that this family may either show autosomal dominant inheritance (see 178110) or that the father is a manifesting heterozygote. In the girl they previously reported, Prontera et al. (2007) performed molecular analysis of coding regions of the CHRNG gene but failed to identify a missense or frameshift mutation.

Seo et al. (2015) reported 2 unrelated Korean families in which 2 sibs each had congenital arthrogryposis multiplex. Features included decreased fetal movements and multiple contractures apparent at birth, as well as vertical tali. One sib died of respiratory infection at age 6 months. Additional features included small mouth, high-arched palate with malocclusion, micrognathia, short neck, and sloping shoulders. The 3 surviving children all had normal intelligence and were able to walk independently.

Inheritance

The transmission pattern of the Escobar variant of multiple pterygium syndrome in the Korean families reported by Seo et al. (2015) was consistent with autosomal recessive inheritance.

Molecular Genetics

Hoffmann et al. (2006) and Morgan et al. (2006) demonstrated that both the lethal and the nonlethal (Escobar) variants of multiple pterygium syndrome can be caused by mutations in the gamma, or fetal, subunit of the nicotinergic acetylcholine receptor (CHRNG; 100730). Hoffmann et al. (2006) found 8 mutations in 7 families with Escobar syndrome. Morgan et al. (2006) found 6 homozygous mutations in 6 families with lethal or Escobar variants. In 1 family both variants were present.

Hoffmann et al. (2006) noted that the congenital contractures characteristic of Escobar syndrome may be caused by reduced fetal movements at sensitive times of development. Possible causes of decreased fetal mobility include space constraints such as oligohydramnion, drugs, metabolic conditions, or neuromuscular disorders including myasthenia gravis (254200). Myasthenia is characterized by intermittent muscle weakness, most commonly caused by autoantibodies binding to nicotinergic acetylcholine receptor (AChR). During pregnancy, autoantibodies may cross the placenta and cause transient muscle weakness or, more seriously, an arthrogryposis-like syndrome. Mutations causing congenital myasthenic syndrome (e.g., 608931) have been identified in subunits of the AChR (e.g., CHRNA1, 100690). The CHRNG gene encodes the gamma subunit of the AChR and is expressed before the 33rd week of gestation in humans but is replaced by the epsilon subunit (100725) in the late fetal and perinatal period, thereby forming the adult AChR. The demonstration that Escobar syndrome and the lethal form of multiple pterygium syndrome can be caused by mutations in CHRNG by Hoffmann et al. (2006) and Morgan et al. (2006) showed that these are examples of dysmorphology caused by the transient inactivation of the neuromuscular end plate. Because CHRNG gene expression is restricted to early development, patients have no myasthenic symptoms later in life. This is the major difference from mutations in the other AChR subunits and the striking parallel to the symptoms found in neonates with arthrogryposis when maternal AChR autoantibodies cross the placenta and cause the transient inactivation of the AChR pathway.

In 3 patients from 2 unrelated Korean families with Escobar syndrome, Seo et al. (2015) identified compound heterozygous mutations in the CHRNG gene (100730.0007 and 100730.0009). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies of the variants were not performed.