Saul-Wilson Syndrome
Summary
Clinical characteristics.
Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech and motor) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy. To date, 16 affected individuals have been reported.
Diagnosis/testing.
The diagnosis of SWS is established in a proband with marked short stature, typical facial and skeletal features, and a heterozygous pathogenic variant in COG4 identified by molecular genetic testing. To date only two COG4 variants, both resulting in a p.Gly516Arg missense change, have been reported.
Management.
Treatment of manifestations: Skeletal dysplasia or physiatry clinic (orthopedist, OT/PT/ rehabilitation specialist) to address repair of clubfoot, possible C1-C2 subluxation and/or spinal cord compression, mobility issues in those with residual foot deformities (post clubfoot repair), osteoarticular pain; standard treatment for feeding issues, speech delay, cataracts and retinal dystrophy, and hearing loss.
Surveillance: Routine follow up of growth and feeding, developmental progress and educational needs, musculoskeletal issues including mobility, osteoarticular pain, bone fragility, possible cataracts and/or retinal dystrophy, hearing loss.
Agents/circumstances to avoid: Participation in gymnastics and jumping on a trampoline until atlanto-axial instability is excluded.
Genetic counseling.
SWS is an autosomal dominant disorder typically caused by a de novo pathogenic variant. Sib recurrence has been observed in one family and is thought to result from germline mosaicism in a parent. The risk to offspring of an individual with SWS of inheriting the COG4 pathogenic variant is 50%. Once the COG4 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
Formal diagnostic criteria for Saul-Wilson syndrome have not been established.
Suggestive Findings
Saul-Wilson syndrome should be suspected in individuals with the following clinical, laboratory, and imaging findings [Ferreira et al 2018].
Clinical findings
- Skeletal
- Profound short stature (typically of prenatal onset)
- Clubfoot
- Short distal phalanges of fingers and toes (Figure 1)
- Distinctive craniofacial features (Figure 1)
- Progeroid facial appearance (more striking during infancy)
- Sparse hair and sparse eyebrows
- Prominent forehead with prominent scalp veins
- Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
- Narrow nasal bridge with convex nasal ridge
- Prominent columella (developing in late childhood)
- Thin vermilion of the upper lip
- Mild micrognathia
- Eyes
- Blue sclerae (during the first few months of life)
- Lamellar cataracts
- Rod-cone dystrophy
- Hearing loss (conductive, sensorineural, and mixed)
- Early developmental delay (primarily speech) with normal cognition
Figure 1
A, C, and D. Note prominent forehead, scalp veins, and columella, as well as thin vermilion of the upper lip. B. Note short distal phalanges of the fingers.
Laboratory findings
- Elevated hepatic transaminases
- Intermittent neutropenia
Skeletal radiographs (Figure 2)
Figure 2
A. Babygram obtained at age 11 months. Note coxa valga, overtubulation of the long bones, and lucencies of the proximal femora. B. Lateral cervical spine radiograph obtained at age eight months highlighting hypoplasia of the odontoid process
- Long bones
- Short long bones
- Overtubulation with thin diaphyses and flared metaphyses
- Lucency of proximal femora
- Coxa valga
- Megaepiphyses
- Hand
- Small hands with short metacarpals and short phalanges
- Accessory ossification centers of the proximal metacarpals
- Cone-shaped epiphyses of the phalanges
- Ivory epiphyses of the distal phalanges (in late childhood)
- Spine
- Hypoplasia of the odontoid process of C2
- Hypoplasia of T12 or L1
- Platyspondyly (vertebral bodies become taller with age)
- Irregularities of the endplates of the vertebral bodies (in later life)
Establishing the Diagnosis
The diagnosis of Saul-Wilson syndrome is established in a proband with marked short stature, typical facial and skeletal features, and a heterozygous pathogenic variant in COG4 identified by molecular genetic testing (see Table 1).
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because Saul-Wilson syndrome is rare, individuals with the distinctive findings described in Suggestive Findings in whom the diagnosis is recognized are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Saul-Wilson syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1: Single-Gene Testing
Sequence analysis of COG4 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected.
Note: (1) Since only two variants, both resulting in a p.Gly516Arg missense change, have been reported to date, targeted analysis for these variants could be performed first to confirm a clinical diagnosis of Saul-Wilson syndrome. (2) Since Saul-Wilson syndrome occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
Option 2: Genomic Testing
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is the most commonly used genomic testing method; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Saul-Wilson Syndrome
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| COG4 | Sequence analysis 3 | 14/14 4 |
| Gene-targeted deletion/duplication analysis 5 | None detected 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Ferreira et al [2018]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Since Saul-Wilson syndrome occurs through a gain-of-function mechanism and large intragenic deletions or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
Clinical Characteristics
Clinical Description
Saul-Wilson syndrome is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy.
A total of 16 individuals with Saul-Wilson syndrome have been reported to date. Saul-Wilson syndrome was first described in a small-for-gestational-age infant with bulging fontanelles, clubfoot, blue sclerae, and blunted fingertips; over time, growth was delayed and the child developed bilateral cataracts, and hearing loss as the result of frequent otitis media [Saul 1982]. Three additional individuals with similar features were reported [Saul & Wilson 1990, Hersh et al 1994]. Subsequently the diagnosis of Saul-Wilson syndrome was entertained in a child without typical facial features [Chinen et al 2015], but the diagnosis could not be confirmed by molecular genetic testing. Fourteen individuals were described in 2018, including two originally reported in the 1990s [Ferreira et al 2018]. Since that publication, a few additional individuals with Saul-Wilson syndrome worldwide have been diagnosed [Author, personal observation]. The clinical findings discussed in this section are based on these reports.
Growth
Individuals with Saul-Wilson syndrome show impaired postnatal growth, and several also had intrauterine growth restriction (IUGR).
Mean length, weight, and head circumference at birth:
- Length. 44.1 cm (range 38.0-49.0)
- Weight. 2.09 kg (range 1.45-2.80)
- Head circumference. 31.7 cm (range 29.0-34.0)
Z-scores at birth:
- Length. -2.3 ± 1.5 SD (range -0.4 to -5.1)
- Weight. -2.4 ± 0.7 SD (range -1.2 to -3.8)
- Head circumference: -2.0 ± 0.9 SD (range -0.8 to -3.9)
Standard deviation scores decline sharply over the first few months of life. At last examination:
- Stature. -6.3 ± 1.8 SD (range -3.5 to -9.8)
- Weight. -4.0 ± 1.2 SD (range -1.1 to -5.8)
- Head circumference. -1.7 ± 1.7 SD (range 0.8 to -5.0)
Based on data available from three adults
- Mean height, weight, and head circumference at skeletal maturity:
- Height. 107.6 cm
- Weight. 30.5 kg
- Head circumference. 50.2 cm
- Z-scores at skeletal maturity:
- Height. -8.9 ± 0.8 SD (range -8.3 to -9.8)
- Weight. -4.3 ± 0.6 SD (range -3.6 to -4.8)
- Head circumference. -3.9 ± 1.6 SD (-2.7 to -5.0)
Growth charts for clinical use are currently under development.
Despite absolute microcephaly, head circumferences exceed the height by more than 2 SD, with consequent relative macrocephaly.
Development
Speech delay (8/11) and motor delay (12/14) are common, probably related to the presence of hearing loss and skeletal deformities, respectively; cognitive development does not appear to be affected.
Ophthalmologic Features
The majority of affected individuals develop lamellar cataracts during the first few years of life (10/13), and several developed retinal involvement (6/9). Retinal pigmentary changes can be seen in the periphery as early as the toddler years. During adolescence and early adulthood, a rod-cone dystrophy (5/9) becomes evident with constricted visual fields and night blindness.
Macular cystic changes were also described (2/4). One individual had myelinated retinal nerve fibers [Ferreira et al 2020].
Skeletal Features
Shortening of the distal phalanges of fingers and toes is appreciated on physical examination (12/14). This finding, apparent at birth, did not progress over time. The majority of individuals (10/14) had clubfoot, and in some cases residual deformity even after multiple attempts at surgical repair [Ferreira et al 2020]. Pectus deformity (5/14) and cervical spinal cord compression (3/7) have also been reported.
Bone fragility has been suggested, as several individuals (4/14) developed fractures with minimal or no known trauma [Ferreira et al 2020]. One of these individuals had poor fracture healing, which was also described in the original patient [Saul & Wilson 1990]. Nonunion with pseudoarthrosis has been seen in two individuals [Saul & Wilson 1990, Ferreira et al 2020]. Although DXA scans for two individuals reported bone mineral density (BMD) <2 SD below the mean, the height-adjusted BMD [Zemel et al 2010, Zemel et al 2011] was normal in both [Author, personal observation].
Osteoarticular pain was reported by all three adults. Two had confirmed degenerative joint disease, leading to joint replacement surgeries in one individual in her 20s [Ferreira et al 2020].
The combination of megaepiphyses with coxa valga, leading to acetabulum-femoral epiphyseal incongruence, may contribute to premature osteoarthropathy of the hip.
Other
Hearing loss, seen in the majority of affected individuals over time, can be conductive, sensorineural, or mixed. In one child hearing impairment associated with inner-ear malformations was detected on newborn hearing screen.
MRI findings. Ventriculomegaly was seen in 5/9 and spinal cord syrinx in 1/4 individuals. Spinal cord compression was observed in 3/7: in one child with soft-tissue pannus surrounding the odontoid process, it was seen as early as age four years, and in another child with cervical spine instability, as late as age 14 years.
Intermittent neutropenia, though not appreciated in the first two months of life, was seen in all 12 individuals subsequently evaluated for this finding [Ferreira et al 2020]. The earliest known age of onset is three months, and it still occurred in adults. While intermittent neutropenia could be one possible explanation for the frequent (although rarely life-threatening) respiratory infections experienced in the first years of life, the neutropenia persisted into adulthood whereas the number of respiratory infections decreased over time.
Asymptomatic elevation of liver transaminases. Elevated aspartate aminotransferase was observed in 6/8 individuals and elevated alanine aminotransferase in 3/8, without abnormalities in other liver function tests, such as serum albumin, coagulation parameters, alkaline phosphatase, and bilirubin [Ferreira et al 2020].
Genotype-Phenotype Correlations
No genotype-phenotype correlation is possible because all affected individuals have the same amino acid substitution.
Penetrance
Penetrance is thought to be 100%.
Prevalence
Sixteen individuals have been reported to date. Three additional individuals are known to have the diagnosis of Saul-Wilson syndrome [Author, personal observation]. There is no known geographic predilection.
Differential Diagnosis
Table 2.
Disorders Interest in the Differential Diagnosis of Saul-Wilson Syndrome
| Differential Disorder | Cause | MOI | Features of Differential Disorder | |
|---|---|---|---|---|
| Overlapping w/SWS | Distinguishing from SWS | |||
| Silver-Russell syndrome | Chromosome 11p15.5- or chromosome 7-related | See footnote 1. |
|
|
| Osteogenesis imperfecta (see COL1A1/2 Osteogenesis Imperfecta) | COL1A1 COL1A2 (>15 genes) 2 | AD 2 |
|
|
| Microcephalic osteodysplastic primordial dwarfism type II (OMIM 210720) | PCNT | AR |
|
|
| Wiedemann- Rautenstrauch syndrome (OMIM 264090) | POLR3A | AR |
|
|
| Hallermann- Streiff syndrome (OMIM 234100) | Unknown | Unknown |
| Distinct facial gestalt (e.g., characteristic thin nose & more pronounced micrognathia) |
| Floating-Harbor syndrome | SRCAP | AD |
| Distinct facial gestalt (e.g., distinctive prominent nose) |
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SWS = Saul-Wilson syndrome
- 1.
In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as the result of an apparent de novo epigenetic or genetic alteration (e.g., loss of paternal methylation at the H19/IGF2 imprinting center 1 or maternal uniparental disomy for chromosome 7).
- 2.
The majority of individuals diagnosed with osteogenesis imperfect (OI) have the disorder as the result of a pathogenic variant in COL1A1 or COL1A2. COL1A1/2-OI is inherited in an autosomal dominant manner. OI caused by pathogenic variants in other genes (see OMIM PS166200) may be associated with autosomal recessive, autosomal dominant, or X-linked inheritance.
- 3.
Intellectual disability is not typically observed in Saul-Wilson syndrome.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Saul-Wilson syndrome, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with Saul-Wilson Syndrome
| System/Concern | Evaluation | Comment |
| Constitutional | Measurement of HT, WT, & HC | Assess for evidence of linear growth failure using SWS-specific growth charts. |
| Gastrointestinal/ Feeding | Gastroenterology / nutrition / feeding team evaluation | Avoid overfeeding. |
| Development | Developmental assessment | To incl motor & speech/language evaluation |
| Musculoskeletal | Refer to physiatry clinic (OT/PT/ rehabilitation specialist). | To evaluate fine & gross motor skills, mobility, & activities of daily living |
| Refer to orthopedist. |
| |
| Obtain history of bone fractures. | ||
| Spine |
| Evaluate for cervical instability & risk of spinal cord compression |
| Eyes | Ophthalmologic evaluation | To incl assessment for rod-cone dystrophy in individuals old enough to cooperate:
Children & adolescents: assess for cataracts. |
| Hearing | Audiologic evaluation 1 | Assess for SNHL & conductive hearing loss. |
| Hematology | Complete blood count w/absolute neutrophil count | To evaluate for neutropenia |
| Liver | Aspartate aminotransferase, alanine aminotransferase | To evaluate for ↑ liver enzymes |
| Miscellaneous/ Other | Consultation w/clinical geneticist &/or genetic counselor | |
| Family support/resources | Assess:
|
BCVA = best-corrected Snellen visual acuity; BMD = bone mineral density; ERG = electroretinography; FTT = failure to thrive; HC = head circumference; HT = height; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; SNHL= sensorineural hearing loss; SWS = Saul-Wilson syndrome; WT = weight
- 1.
See Hereditary Hearing Loss and Deafness Overview for details about audiologic evaluations.
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with Saul-Wilson Syndrome
| Manifestation/ Concern | Treatment | Considerations/Other |
|---|---|---|
| Delayed development | See Developmental Delay Management Issues. | |
| Musculoskeletal | Skeletal dysplasia or physiatry clinic (orthopedics, OT/PT/ rehabilitation specialist) | Address mobility issues in those w/residual foot deformities (post-club foot repair), osteoarticular pain. |
| Cervical spine compression | Surgical mgmt for medullopathy (C1-C2 fixation) by an expert familiar w/skeletal dysplasias & spine involvement | Given possibility of C1-C2 subluxation &/or spinal cord compression, follow best practices in perioperative mgmt of those w/skeletal dysplasias. 1 |
| Cataract / Retinal dystrophy | Standard treatment(s) as recommended by ophthalmologist | Cataracts: Consider surgery when dense to prevent amblyopia Retinal dystrophy:
|
| Hearing loss | Per treating otolaryngologist:
| Community hearing services through early intervention or school district 4 |
| Neutropenia | Per treating immunologist or infectious disease specialist | If frequent infections: consider GCSF to improve absolute neutrophil counts. 5 |
| Family/ Community |
| Consider involvement in adaptive sports or Special Olympics. |
GCSF = granulocyte colony-stimulating factor; OT = occupational therapist; PT = physical therapist
- 1.
White et al [2017]. Including cervical spine imaging prior to general anesthesia.
- 2.
See Nonsyndromic Retinitis Pigmentosa Overview for information about management.
- 3.
In the US, publicly funded agencies at the state level provide services for the visually impaired or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.
- 4.
See Hereditary Hearing Loss and Deafness Overview for information about management.
- 5.
Ferreira et al [2020]
Developmental Disability Management Issues
The following information represents typical management recommendations for individuals with developmental disability in the United States; standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- Individualized education plan (IEP) services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- As required by special education law, children should be in the least restrictive environment feasible at school and included in general education as much as possible and when appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Surveillance
Table 5.
Recommended Surveillance for Individuals with Saul-Wilson Syndrome
| System/Concern | Evaluation | Frequency |
|---|---|---|
| Constitutional |