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.

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 (See Figure 1.)
• Distinctive craniofacial features (See 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 (See 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 (or likely pathogenic) variant in COG4 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous COG4 variant of uncertain significance does not establish or rule out the diagnosis.

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).

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.

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.

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.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

Participation in gymnastics and jumping on a trampoline should be avoided until atlanto-axial instability is excluded.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy of an affected woman has not been documented to date, although regular menstrual cycles and a normal hormone profile in two adult females suggest no impairment of the ability to conceive [Ferreira et al 2020].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Saul-Wilson syndrome is an autosomal dominant disorder typically caused by a de novo pathogenic variant.

Risk to Family Members

Parents of a proband

• No individual with Saul-Wilson syndrome reported to date has had an affected parent.
• Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
• If the COG4 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred de novo in the proband. Another possible explanation is germline mosaicism in a parent. Parental germline mosaicism is presumed in one family with two affected sibs.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the COG4 pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known SWS-related COG4 pathogenic variant that cannot be detected in the leukocyte DNA of either parent or the parents have not been tested for the COG4 pathogenic variant but are clinically unaffected, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with SWS has a 50% chance of inheriting the SWS-related COG4 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

Prenatal Testing and Preimplantation Genetic Testing

Once the COG4 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

COG4 is a subunit of the conserved oligomeric Golgi (COG) complex, a hetero-octameric protein complex that regulates vesicular trafficking between the Golgi apparatus and the endoplasmic reticulum (ER).

Mechanism of disease causation. The distinct phenotypes, recurrent nature of the p.Gly516Arg variant, and accelerated (not delayed) retrograde Golgi-to-ER transport seen in cells support Saul-Wilson syndrome occurring through a gain-of-function mechanism [Ferreira et al 2018].

Revision History

• 20 February 2020 (bp) Review posted live
• 4 October 2019 (cf) Original submission

Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the GeneReview "Saul-Wilson Syndrome" is in the public domain in the United States of America.

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