Liu WL, He ZX, Li F, Ai R, Ma HW. Schinzel-Giedion syndrome: a novel case, review and revised diagnostic criteria. J Genet. 2018 Mar;97(1):35-46. PMID: 29666323.
Abstract
Schinzel-Giedion syndrome (SGS) is a rare autosomal dominant inheritance disorder. Heterozygous de novo mutations in the SETBP1 gene have been identified as the genetic cause of SGS. Here, we report a novel case with the syndrome with a novel insertion mutation in SETBP1. We also present a review of SGS cases, and first revise diagnostic criteria of SGS based on clinicalfindings and/or SETBP1 mutation worldwide. A revised diagnostic criteria and typing of SGS can be determined. Type I (complex and classic type) SGS patients present a development delay and typical facial features (prominent forehead, midface retraction, and short and upturned nose) associated with hydronephrosis or two of the characteristic skeletal anomalies (a sclerotic skull base, wideoccipital synchondrosis, increased cortical density or thickness, and broad ribs). Type II (middle type) patients show development delay and the distinctive facial phenotype (midface retraction, short and upturned nose), lacking both hydronephrosis and typical skeletal abnormalities, with existence of SETBP1mutation. Type III (simple type) patients with SETBP1 alteration show their major symptom is development delay, in which expressive language delay is the most striking feature. Central nervous system involvement with development delay in which expressive language delay is much more obviously affected is the most prominent feature of SGS. There is another indication that severity of phenotype of SGS may be inversely correlated with degree of SETBP1 alteration, besides gain-of-function or dominant-negative effects in SETBP1 alteration causing SGS.
Duis J, van Bon BWM. Schinzel-Giedion Syndrome. 2024 Mar 7. In: Adam MP, Bick S, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. PMID: 38452171.
Excerpt
Clinical characteristics: Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a SETBP1 mutational hot spot, is characterized by global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), hypotonia, spasticity, dysautonomia, hearing loss, and cerebral visual impairment. Other findings can include poor weight gain often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance. Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain. Anomalies of the liver, spleen, and/or pancreas are less common. Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
To date, more than 50 individuals have been reported with molecularly confirmed classic SGS.
Atypical SGS, reported in five individuals to date, is caused by pathogenic SETBP1 variants in proximity to – but not within – the mutational hot spot. The broad spectrum of clinical features of variable severity partially overlaps with classic SGS; however, this spectrum does not include risk for neuroepithelial neoplasia to date.
Diagnosis/testing: The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic gain-of-function variant within the mutational hot spot (i.e., a 12-base-pair region in exon 4 encoding a canonical degron). The diagnosis of atypical SGS syndrome is established in a proband with suggestive findings and a heterozygous SETBP1 pathogenic variant adjacent to – but not within – the mutational hot spot.
Management: Treatment of manifestations: There is no cure for classic or atypical SGS. Supportive treatment to improve quality of life, maximize function, and reduce complications can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology, oncology, urology, nephrology, audiology, gastroenterology, orthopedics, cardiology, and medical genetics.
Surveillance: At each visit, evaluate for feeding issues (including nutritional status and safety of oral intake), gastrointestinal issues, respiratory issues, neurologic manifestations (including seizures, changes in tone, movement disorders, mood, irritability, and alertness), kidney and urinary tract manifestations, and musculoskeletal manifestations. In individuals with classic SGS, age-related surveillance for occurrence of neoplasia includes liver ultrasound and serum alpha-fetoprotein levels, renal ultrasound examination, pelvic MRI for sacrococcygeal teratoma, and monitoring for clinical signs of leukemia.
Agents/circumstances to avoid: Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal impairment from recurrent pyelonephritis and structural renal anomalies.
Genetic counseling: Classic and atypical SGS are autosomal dominant disorders typically caused by a de novo SETBP1 pathogenic variant. Rarely, individuals diagnosed with SGS have the disorder as the result of a pathogenic variant inherited from a parent. Sib recurrence of clinically defined classic SGS, presumed to be due to parental germline mosaicism, has been reported in two families. Transmission of a SETBP1 pathogenic missense variant from an unaffected parent to a child with atypical SGS has been reported in one family (of note, the possibility of mosaicism in the unaffected parent was not excluded). Once the SETBP1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Morison LD, Summerfield N, Bradley D, van Bon BW, Morgan AT. Schinzel-Giedion syndrome: communication, feeding and motor skills in 16 individuals. Neurogenetics. 2025 Aug 27;26(1):64. doi: 10.1007/s10048-025-00846-3. PMID: 40859069; PMCID: PMC12380911.
Abstract
Schinzel-Giedion Syndrome (SGS) is a rare neurodevelopmental disorder caused by pathogenic SETBP1 gain-of-function variants. SGS medical features have been well described. Associated skills critical to quality of life have such as communication, feeding, and motor skills are yet to be characterised. Here we used standardised caregiver report tools to characterise these skills as well as the medical features, in 16 children with SGS (median = 5 years, 7 months, range 6 months to 12.5 years). Vineland-3 scores reflected severe impairment in communication, daily living, socialisation and motor skills. Average receptive and expressive language skills were equivalent to a 0-to-1-month-old. Average motor skills were slightly stronger with age equivalents of 2-months-old for gross motor skills and 4-months for fine motor skills. 13/16 (81%) children could attend to someone's voice, and 15/16 (94%) could make happy vocalisations. One individual (6%) could follow basic instructions. Despite a relatively homogenous phenotype, some children presented with relative strengths when compared to the rest of the cohort. Our expanded phenotype of SGS allows better targeted therapies and supports, highlighting the importance of early feeding intervention and augmentative and alternative communication (e.g., assistive technology for communication). Given the severity of the SGS profile, our data highlight the need for sensitive measurement tools for detecting subtle skill changes in SGS in response to precision medicine interventions.
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