Saul-Wilson Syndrome
A number sign (#) is used with this entry because of evidence that Saul-Wilson syndrome (SWILS) is caused by recurrent de novo heterozygous missense mutations in the COG4 (606976) gene on chromosome 16q22.
DescriptionSaul-Wilson syndrome is a rare skeletal dysplasia with characteristic dysmorphic and radiographic findings, as well as early developmental delay, primarily involving speech, with eventual normal cognition. Clinical findings include marked short stature, prominent forehead with an enlarged anterior fontanel, prominent eyes with cataracts, narrow nasal bridge with a convex nasal ridge, micrognathia, clubfoot, brachydactyly, and short distal phalanges of fingers. Radiographic changes include platyspondyly, irregular end plates of vertebral bodies, and hypoplasia of the odontoid process with cervical instability in the spine, coxa valga, overtubulation, metaphyseal flaring and megaepiphyses in the long bones, while the hands and feet exhibit short phalanges, metacarpals and metatarsals, cone-shaped epiphyses of phalanges, and accessory ossification centers of metacarpals and metatarsals (summary by Ferreira et al., 2018).
Clinical FeaturesSaul (1982) described a 7-year 10-month-old white boy who was born at 34 months' gestation with normal weight, open bulging fontanels, and a left calcaneovalgus deformity. He developed short stature, borderline microcephaly, distinctive facial features including a sharp narrow face, frontal bossing, metopic depression, blue sclerae, bilateral cataracts, and opalescent teeth, pectus carinatum, upper lumbar lordosis, short hands with blunted fingers, and bilateral bowed legs. He had delayed growth, late onset of speech, and delayed gross motor development. Radiographic features included a few wormian bones, widened clavicles, dysplastic L-1 vertebra, nonunion or pseudoarthrosis of the left tibia and fibula, and mild distal phalangeal tufting. Fibroblast enzymes, including arylsulfatase A, alpha-mannosidase, alpha-fucosidase, beta-galactosidase, N-acetyl-beta-glucosaminidase, beta-glucuronidase, prolyl hydroxylase, and lysyl hydroxylase were all normal, as was the sweat chloride.
Saul and Wilson (1990) provided follow-up on the boy (patient 1) previously reported by Saul (1982) and reported an unrelated boy (patient 2) with similar features. At age 16 years, patient 1 showed resolution of his early delay in language and gross motor development and was doing well in school. His height, weight and occipitofrontal circumference (OFC) were all well below the 3rd centile for age but were proportionate. Patient 2 was born at 36 weeks' gestation and weighed only 1.5 kg. Neonatal abnormalities included large anterior fontanel, bilateral clubfoot, contractures of the knees and elbows, and poor feeding. In early childhood he had recurrent otitis media and several episodes of pneumonia requiring hospitalization. His psychomotor development was delayed. At age 9 years he had a vocabulary of only a few words; when excited, he hand flapped. Hearing tests were normal. His height, weight, and OFC were all well below the 3rd centile for age but proportionate. Craniofacial manifestations included frontal prominence with slight metopic depression, a small recessed midface with a narrow nasal root, beaked nose, and prominent eyes. The chin was small and teeth were crowded and slightly opalescent. Chest was narrow superiorly but flared at the costal margins. All major joints had full range of motion except the ankles of which there was slight limitation. Hands and fingers were short and the fingers were broad distally. Nails were short and broad. X-rays showed short phalanges with widening of the distal phalanges, several coned epiphyses, and sclerotic epiphyses with a normal bone age. Hip radiographs showed coxa valga. Both patients had mild widening of the medial ends of the clavicles as well as several vertebral irregularities, including a dysplastic L-1 in patient 2.
Hersh et al. (1994) reported 2 additional unrelated patients with similar clinical and radiographic features. Patient 1 was a girl who was noted at birth to have a large anterior fontanel, sparse scalp hair, a high forehead, slight exophthalmos, beaked nose, micrognathia, and clubfeet. In infancy, she had hypotonia and recurrent otitis media. She developed cataracts at age 3. An MRI at age 2 years documented a syrinx of the lower spinal cord and tethered cord necessitating surgical treatment. The patient walked at age 2 years and acquired normal speech and language. At age 4.5 years, her height, weight, and OFC were all less than the 5th centile. Facial features included prominent forehead with shallow supraorbital ridges, midface hypoplasia, micrognathia, and blue sclerae. She had slightly prominent ears, a narrow nasal root, a beaked nose, and bifid uvula. Dentition was normal. She had pectus excavatum. She had brachydactyly with short hands and short midfinger length. There was blunting of the fingertips, and talipes equinovarus was present with atrophy of the gastrocnemius muscles. The elbows were prominent and extension was limited to 165 degrees. There was an exaggerated lumbar lordosis and capillary hemangioma. Skeletal survey documented moderate flattening of the vertebral bodies. The first lumbar vertebra was hypoplastic with a wedge-shaped appearance. There was hypoplasia of the odontoid process, and a coxa valga deformity was present bilaterally. There was overtubulation of the long bones, with relative flare of the metaphyses. The metacarpals, metatarsals, and phalanges were short. Several epiphyses of the fingers were cone shaped, and ivory epiphyses were present in the distal phalanges of the fingers. Patient 2 was a boy born at 36 weeks' gestation with height, weight, and OFC at the 50th centile. He had wide anterior fontanel, a prominent nasal bridge, micrognathia, and mild symmetrical rhizomelic shortness of all limbs. Skeletal survey disclosed platyspondyly with mild coronal clefting. There was rhizomelic and mesomelic shortness of long bones. He had multiple episodes of otitis media as well as multiple hospitalizations for aspiration pneumonia. Gastroesophageal reflux was identified and a fundal plication was performed. Growth hormone studies were normal. Audiometry studies showed mild mixed bilateral hearing loss, and there was evidence of global developmental delay with greater speech delay. Iliac crest bone biopsy showed normal resting cartilage, but some chondrocytes appeared to have large inclusion bodies within them. At age 5 years, the patient's height and weight were at the 50th percentile for a 9-month-old infant, and OFC was at the 50th centile for an 18 month old. He had a striking facial appearance with frontal bossing, downslanting palpebral fissures, blue sclerae, shallow orbits with prominent eyes, narrow nasal root with beaked nose, and micrognathia. There was a mild lenticular opacity in the left eye. He had pectus carinatum. There was mild lower thoracic scoliosis and accentuated lumbar lordosis. There was evidence of metatarsus adductus, and his fingers were short with squared distal phalanges. There was limitation of movement at the elbow joint.
Ferreira et al. (2018) reported 14 patients with Saul-Wilson syndrome, including patient 2 in the report of Saul and Wilson (1990) and patient 1 in the report of Hersh et al. (1994). The patients ranged in age from 18 months to 39 years, were of various ethnicity, and included 6 females. Birth weight Z score ranged from -1.2 to -3.8, birth length Z score from -0.7 to -5.1, and birth OFC Z score from -0.8 to -3.9. Current weight Z scores ranged from -1.1 to -5.8, height Z score from -3.5 to -9.8, and OFC Z score from +0.8 to -5. Ferreira et al. (2018) noted that all 14 patients had prominent forehead, prominent veins, prominent eyes, overtubulation of the long bones, metaphyseal long bone flaring, megaepiphyses, coxa valga, and short metatarsals, metacarpals, and phalanges. Most patients had anterior fontanel enlargement or delayed closure, dens hypoplasia, micrognathia, neutropenia, cataracts, hearing loss that was bilateral sensorineural, mixed, or conductive, irregular vertebral bodies, many of which were described as mild and some only at an older age, cone-shaped epiphyses, pseudoepiphyses of the metacarpals, ivory epiphyses of the phalanges, and clubfoot.
Molecular GeneticsIn 14 patients with Saul-Wilson syndrome, including patient 2 in the report of Saul and Wilson (1990) and patient 1 in the report of Hersh et al. (1994), Ferreira et al. (2018) identified 2 different de novo heterozygous mutations in the COG4 gene, c.1546G-A (606976.0005) and c.1546G-C (606976.0006), both of which give rise to an identical missense mutation (G516R). The mutations, which were found by whole-exome or whole-genome sequencing, were confirmed by Sanger sequencing. Compared to control cell lines, fibroblasts from affected individuals showed normal mRNA expression and protein level of COG4 and other COG subunits, confirming that the variant leads to production of a stable protein. Protein modeling predicted the loss of a loop structure in the mutant protein; however, binding of COG4 to other COG subunits was not altered.
PathogenesisFerreira et al. (2018) found that Golgi morphology was significantly altered in fibroblasts of 3 patients with Saul-Wilson syndrome with only 51.1% (n=237, patient 1.1), 52.8% (n=254, patient 4.1), and 54.9% (n=268, patient 5.1) of the Golgi complexes exhibiting normal morphology in contrast to 93.9% in control fibroblasts. Abnormal Golgi morphology was defined as colocalization of GM130 (GOLGA2; 602580) and TGN46 (TGOLN2; 603062), suggesting collapse of the cis- and trans-Golgi stacks. The Golgi volume in patient cells was significantly decreased compared to that of control cells (P less than 0.0001). The nuclear volume was also decreased (P = 0.0016). Ferreira et al. (2018) found that unlike patients with CDG2J (613489) due to biallelic mutation in COG4 who demonstrate delayed response to brefelden A treatment, patients with SWILS have significantly faster brefeldin A-induced retrograde transport.
Animal ModelFerreira et al. (2018) used CRISPR/Cas9 to knock out cog4 in zebrafish and found that the cog4-null mutants had inner ear, growth, and skeletal defects.