Ulna And Fibula, Absence Of, With Severe Limb Deficiency

A number sign (#) is used with this entry because of evidence that the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome is caused by homozygous mutation in the WNT7A gene (601570) on chromosome 3p25.

Description

The Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome (AARRS) is a rare autosomal recessive disorder characterized by severe malformations of upper and lower limbs with severely hypoplastic pelvis and abnormal genitalia. The disorder is believed to represent a defect of dorsoventral patterning and outgrowth of limbs (summary by Kantaputra et al., 2010).

Clinical Features

In a daughter and son of consanguineous Jordanian parents, Al-Awadi et al. (1985) described a syndrome of severe deficiency of all 4 extremities. Both had hypoplastic femora and absent ulnae and fibulae. Although 'thoracic dystrophy,' pelvic deformity, and unusual facies were mentioned, these did not seem as impressive as the limb malformations. The authors thought this did not fit any previously described condition. Al-Awadi et al. (1985) concluded that the disorder in their patients was different from that reported by Kuhne et al. (1967); see 228200. Teebi (1993) reported that absence of the uterus was found upon reevaluation of the girl described by Al-Awadi et al. (1985). Richieri-Costa (1987) described a sporadic case of this association in a Brazilian girl. Raas-Rothschild et al. (1988) described another family, in which the 3 offspring (a boy and 2 fetuses) of double first-cousins of Oriental-Jewish ancestry were affected. One of the fetuses had occipital meningocele. The authors provided a review of autosomal recessive disorders with limb malformations. Farag et al. (1993) reported the disorder in a Bedouin infant whose parents and grandparents were consanguineous. The infant had mullerian aplasia. Intellectual development at 6 months was normal. Camera et al. (1993) described the same disorder in 2 Italian sibs who also showed very dysplastic, large ears, a high and narrow palate, and pseudarthrosis of the right clavicle. They proposed the designation Al-Awadi/Raas-Rothschild syndrome for this disorder.

Schinzel (1990) described 2 female infants with phocomelia of both lower extremities with 4-toed feet. The older sister had also phocomelia of the left upper extremity and diaphragmatic hernia. The younger sister showed also a defect of the occipital bone, agenesis of the uterus and vagina, and hypoplasia of the sacrum. Chitayat et al. (1993) reported a girl of Panamanian origin with bilateral lower limb phocomelia with 3-toed feet, hypoplastic sacrum, and absence of the uterus and left ovary. The next pregnancy of the couple was terminated because of fetal acrania. Chitayat et al. (1993) noted the similarity between their patient and the patients reported by Schinzel (1990) and proposed the designation 'Schinzel-phocomelia syndrome.' Lurie and Wulfsberg (1993) showed that Al-Awadi/Raas-Rothschild syndrome and Schinzel-phocomelia syndrome are most likely different names for the same disorder, which includes skeletal defects, mullerian a- or hypoplasia, and occipital meningocele.

Olney et al. (2001) reported an additional patient with Schinzel phocomelia syndrome. The infant had quadrilateral intercalary limb deficiencies, preaxial toe polydactyly, absent pelvis, large parietooccipital skull defect with no underlying brain abnormality, and extraskeletal anomalies including microtia, telecanthus, micropenis with cryptorchidism, renal cysts, stenosis of the colon, and a cleft alveolar ridge. The authors emphasized the skull and pelvis defects which assist in differentiating this condition from others with intercalary limb deficiencies. Absence of the pelvis, as was noted on prenatal ultrasound, may suggest this condition prenatally.

Kantaputra and Tanpaiboon (2005) reported on a 3-year-old Thai boy with limb, pelvic, and genital malformations similar to those of AARRS. The upper limbs were more severely affected than the lower ones. Unlike the findings in AARRS, the radial ray was more severely affected than the ulnar ray. The presence of humeroulnar synostosis and humero-ulnar-radial synostosis and the absence of a radius was thought to distinguish the disorder from AARRS. The penis was unremarkable; however, there was absence of scrotum, and testes were neither palpable nor detectable by ultrasonography.

Woods et al. (2006) investigated a family with 3 children diagnosed with absence of ulna and fibula with severe limb deficiency. The first child exhibited ectrodactyly of the right hand, with nail dysplasia; contractures at the right elbow joint; no left elbow joint, with the left arm ending with an appendage that looked like a deformed finger with dysplastic nail; and lower limbs replaced by a stick-like appendage (more severe on the right side). The second child had complete absence of the lower limbs, and both upper limbs lacked an elbow joint and ended with a deformed finger-like appendage with dysplastic nails. Both children had normal intelligence and health.

Lonardo et al. (2007) reported 2 fetuses, born of nonconsanguineous parents, with features consistent with AARRS. Findings not previously reported included cleft palate and structural gastrointestinal abnormalities. Lonardo et al. (2007) also provided a review of the literature and proposed that diagnostic criteria for the syndrome include longitudinal/intercalary reduction of all 4 limbs, oligodactyly, and hypoplasia of the pelvis.

Subhani et al. (2009) described a girl with AARRS who had pelvic, femoral, and tibial hypogenesis with absent fibula, subtle facial changes, patent foramen ovale, single umbilical artery, single kidney, imperforate anus with rectal fistula in the vaginal fourchette, and asymmetric ambiguous external genitalia. Subhani et al. (2009) suggested that AARRS, Fuhrmann syndrome (228930), and similar conditions comprise a spectrum, and that the anomaly pattern derives from serial action of the same signal pathways within primary (e.g., the major axes), secondary (e.g., heart or limb primordia), and/or local (e.g., tibial-fibular differentiation) developmental fields.

Garavelli et al. (2011) suggested that Schinzel phocomelia and AARRS represent different entities because the hands and feet, as the most distal structures, are relatively unaffected in Schinzel phocomelia, whereas in AARRS the distal element is always more severely affected. However, the 2 Thai sisters described by Kantaputra et al. (2010) with mutations in the WNT7A gene presented different foot malformations: one had stick-like lower limbs as in AARRS, and the other had feet with soft dorsal parts with characteristics of soles and absent or severely hypoplastic nails as in Schinzel phocomelia.

Mapping

By homozygosity mapping, Woods et al. (2006) mapped the phenotype in the family they described to chromosome 3p25.1.

Molecular Genetics

Woods et al. (2006) considered the WNT7A gene a candidate for causative mutations in the family described by them because of its location in the linkage region and because of its known involvement in limb development. They identified a single homozygous missense mutation in exon 4, 1179C-T, that led to an R292C amino acid substitution (601570.0001).

In 2 Thai sisters with short and malformed long bones, absent fibulae, flexion contracture of digits, and hypoplastic/aplastic nails, Kantaputra et al. (2010) identified homozygosity for a missense mutation in the WNT7A gene (R222W; 601570.0004). The authors noted that both sisters exhibited fusion between the severely malformed femora and slender tibiae, a feature that had not previously been reported with WNT7A mutations.

In an affected brother and sister and their female cousin with variable limb reduction phenotypes, all born of consanguineous marriages within a Saudi Arabian family, Eyaid et al. (2011) identified homozygosity for a missense mutation in the WNT7A gene (G204S; 601570.0003). All 3 patients had pelvic hypoplasia and truncated appendages replacing the lower limbs, but the upper limb phenotype ranged from absence of the ulna with a short radius and 1 missing digit per hand to a single bone with absence of elbow joint and only 2 digits per hand to total absence of the upper limbs (amelia).

Garavelli et al. (2011) reported a child with the AARRS phenotype who was homozygous for a mutation in the WNT7A gene (E72K; 601570.0005).