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.

Suggestive Findings

Schinzel-Giedion syndrome (SGS) should be considered in a proband with the following clinical findings and family history.

Clinical findings

• Moderate-to-profound developmental delay (DD) or intellectual disability (ID)
• Facial features include a prominent forehead, midface retrusion, and bitemporal narrowing with or without other characteristics features (see Figure 2). Although facial features are typical in both classic and atypical SGS, the facial features in individuals with atypical SGS are not as coarse.

Figure 2.

Characteristic facial features in individuals with Schinzel-Giedion syndrome (SGS), including prominent forehead, bitemporal narrowing, midface retrusion, hypertelorism, infraorbital crease, short nose with upturned nasal tip, and low-set, abnormally (more...)

AND any of the following features presenting in infancy or childhood:

• Tone abnormalities (including hypotonia or spasticity)
• Feeding difficulties
• Swallowing difficulties (laryngomalacia, choanal stenosis)
• Epilepsy (multiple types of seizures)
• Microcephaly
• Cerebral vision impairment (CVI), broadly defined here as bilateral visual impairment due to non-ocular causes (i.e., based in the brain) in the presence of normal pupil reactivity
• Hearing impairment, mainly sensorineural hearing loss and less commonly conductive hearing loss
• Congenital anomalies of the kidney and urinary tract, such as hydronephrosis, ureteral anomalies, and renal cysts
• Genital anomalies (in males: hypospadias and hypoplastic scrotum; in females: hypoplastic labia)
• Cardiac anomalies, the majority of which are atrial septal defects, patent ductus arteriosus, and patent foramen ovale
• Skeletal features, including sclerotic base of the skull, wide supraoccipital-exoccipital synchondroses, broad ribs, increased cortical density or thickness, hypoplastic distal phalanges, and talipes equinovarus
• Neoplasia (reported in classic SGS only to date) that may be benign or malignant. The majority of neoplasias are of neuroepithelial origin (mainly sacrococcygeal teratomas). Depending on their location, tumors may also cause obstructive problems.

Family history. Because SGS is typically caused by a de novo pathogenic variant, most probands represent a simplex case (i.e., a single occurrence in a family).

Establishing the Diagnosis

Clinical Description

Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder, is characterized by a range of physical and developmental abnormalities. The main features include global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), tone abnormalities, dysautonomia, and cerebral visual and hearing impairment. Poor weight gain is common and 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. Rarely there may be anomalies of the liver, spleen, and/or pancreas. 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 [Hoischen et al 2010, Suphapeetiporn et al 2011, Lestner et al 2012, Ko et al 2013, Carvalho et al 2015, Herenger et al 2015, López-González et al 2015, Miyake et al 2015, Takeuchi et al 2015, Volk et al 2015, Hishimura et al 2016, Acuna-Hidalgo et al 2017, Bulut et al 2017, Leonardi et al 2020, Leone et al 2020, Sullivan et al 2020, Yang et al 2022].

In addition, more than 40 individuals with the clinical diagnosis of SGS were reported in the medical literature before pathogenic variants in SETBP1 were identified to cause SGS [Lehman et al 2008].

Atypical SGS, caused by SETBP1 pathogenic variants in proximity to – but not within – the mutational hot spot, has a broad spectrum of clinical features of variable severity that partially overlap with classic SGS, but do not include risk for neuroepithelial neoplasia to date. Five individuals with atypical SGS have been reported to date.

The following clinical description is mainly based on reports of individuals with molecularly confirmed classic SGS (see Table 3).

Developmental delay (DD) and intellectual disability (ID). Moderate-to-severe (in classic SGS) or mild-to-severe (in atypical SGS) developmental delay and intellectual disability are present in all individuals reported to date. The majority of individuals with classic SGS have no speech and never develop the ability to walk independently.

Epilepsy may start in the neonatal period or later. The heterogeneous seizure types include tonic, tonic-clonic, myoclonic, or partial motor seizures and infantile epileptic spasms syndrome (IESS) (seen in about 25% of individuals). EEG findings often show multifocal spikes or hypsarrhythmia. Epilepsy is reported less frequently in individuals with atypical SGS than in individuals with classic SGS.

Most seizures are refractory to treatment with anti-seizure medications (ASMs), adrenocorticotropic hormone, steroids, and the ketogenic diet.

Hypotonia and spasticity are common and may occur at different times in the same individual. While hypotonia is common at birth, spasticity may develop at a later age and progress. Differences in muscular tone may also lead to spinal deformities such as scoliosis.

Cerebral vision impairment has been reported in 70%-80% of individuals with classic SGS and may also occur in atypical SGS.

Feeding difficulties may be due to underlying factors including hypotonia, sucking problems due to micrognathia, swallowing problems, trachea- and/or laryngomalacia, gastroesophageal reflux disease, and/or vomiting.

Hearing impairment occurs in nearly 90% of individuals with classic SGS and may also occur in atypical SGS. While the type of hearing loss can vary among affected individuals, bilateral sensorineural hearing loss is most common, ranges from mild to profound, and can differ in each ear.

Other reported types of hearing loss include mixed or conductive hearing loss. For example, mixed moderate hearing loss was reported in two individuals due to bilateral deformations of the stapes (that had a tuning fork shape) and in one individual with a flattened last cochlear spire (identified by temporal bone CT scan) [Minn et al 2002, Herenger et al 2015].

Ophthalmologic involvement. Abnormalities of the optic nerve (small optic discs, optic disc pit), strabismus, and alacrima with corneal hypoesthesia have been reported.

Skeletal findings. Anomalies identified on skeletal radiographs can include sclerotic base of the skull with a wide occipital synchondrosis, a poorly mineralized rest of the cranium, a wide anterior fontanelle, and wormian bones. Additional findings can include broad ribs, scoliosis, bowed long bones, short pubic rami, wide pubic symphysis, and hypoplastic distal phalanges in the hands and feet. Individuals often show a typical posture with clenched hand (see Figure 1). Talipes equinovarus is common.

Figure 1.

Characteristic hand posture with clenched hand in an individual with Schinzel-Giedion syndrome Adapted with permission from Acuna-Hidalgo et al [2017]

Postaxial polydactyly (predominantly of the hands) was noted in about 5%-10% of individuals with classic SGS.

Congenital anomalies of the kidney and urinary tract. Bilateral or unilateral hydronephrosis, ranging from mild pyelectasis to severe hydronephrosis, is common in individuals with classic SGS. Hydronephrosis may be present on prenatal ultrasound examination; however, it may not be present at birth but rather develop during infancy. Two individuals with atypical SGS have had medullary cystic kidneys, mild pyelectasis, and chronic urinary infections.

Stenosis of the ureteropelvic junction or vesicoureteral reflux are common. Bladder atony may be the cause of frequent and persistent urinary tract infections.

Other anomalies can include abnormal ureters and renal cysts.

One individual had bilateral large coralliform (i.e., resembling the calyx cavities) renal stones that were predominantly calcium oxalate and calcium phosphate without pyelic dilatation [Herenger et al 2015].

Genital anomalies. The majority of individuals with classic SGS have genital anomalies. In males, these include micropenis (which may appear as ambiguous genitalia on antenatal ultrasound examination), hypospadias, hypoplastic scrotum, and cryptorchidism. In females, these include bifid uterus, hypoplastic uterus, hypoplastic labia majora or minora, and deep labial sulcus. The perineum is often short with an anteriorly displaced anus [Lehman et al 2008].

Cardiac defects. The majority of cardiac defects are atrial septal defects, persistent foramen ovale, and patent ductus arteriosus. Other cardiac findings that occur occasionally include hypoplasia of ventricles and cardiac hypertrophy.

Neoplasia. About 25% of individuals with classic SGS develop a neoplasia, often of neuroepithelial origin. To date, SGS-related neoplasia has not been reported in individuals with atypical SGS caused by SETBP1 pathogenic variants outside of the mutational hot spot. Neoplasias may be detected at birth, during the first year of life, or later in life (e.g., malignant degeneration of a multicystic dysplastic kidney) [Matsumoto et al 2005].

Sacrococcygeal teratoma is the most common tumor. Other reported tumors include hepatoblastoma, lumbosacral teratoma, lumbosacral primitive neuroectodermal tumor, Wilms tumor, and extradural ependymomas. To date, juvenile myelomonocytic leukemia has been reported in one individual [Acuna-Hidalgo et al 2017].

Although most children with SGS die from other causes, a 24-month-old child died of organ failure due to a sacrococcygeal teratoma and a five-year-old child died due to relapse of an extradural ependymal tumor [Acuna-Hidalgo et al 2017].

Other findings

• Microcephaly has been observed in approximately 80% of individuals with classic SGS. In most reported individuals, microcephaly is postnatal – although the occipital-frontal circumference may be within normal limits at birth (almost always below the 50th and often near the 10th centile), head growth decelerates and microcephaly develops during infancy.
• Structural brain abnormalities vary. Most common are partial or complete agenesis of the corpus callosum. Other findings can include progressive cortical atrophy, ventricular anomalies, hydrocephalus, cortical abnormalities, delayed myelination, and choroid plexus cysts.
  In one individual, an abnormal posterior fossa with stretching of the pituitary stalk resulted in central diabetes insipidus and central hypothyroidism [Santos et al 1994].
• Respiratory abnormalities. Structural abnormalities that may lead to breathing and swallowing difficulties include choanal stenosis, micrognathia, tracheobronchomalacia, and lung hypoplasia. Difficulty managing oral and respiratory secretions resulting from progressive gingival hypertrophy and/or excessive mucus production may be additional factors that increase the risk of aspiration and respiratory infections including pneumonia.
• Gastrointestinal problems. Constipation, gastroesophageal reflux disease, and aspiration are common. Chronic vomiting and gastroparesis may also occur. Anteriorly placed anus is often associated with genital anomalies in males and females.
• Structural anomalies of internal organs, such as hypoplasia of the pancreatic tail, annular pancreas, splenopancreatic fusion, and hepatosplenomegaly have been reported.
  Postmortem microscopic evaluation of the pancreas in a four-day-old infant showed dilated interlobular ducts, filled with eosinic mucus and surrounded by abundant connective tissue. Additionally, dilated glands and mucus depositions were found in larynx and bronchial glands; although these findings were like those observed in cystic fibrosis, CFTR testing was normal [Acuna Hidalgo et al 2017].
• Skin. Generalized hypertrichosis that is common at birth may recede during infancy. Facial hemangiomata are present in 25% of individuals with classic SGS. Other features may include dry erythematous skin, redundant nuchal skin, cutis marmorata, hypoplastic nipples, hyperconvex nails, and hypoplastic dermal ridges.
• Dental findings include hypodontia, delayed teeth eruption, and congenital thickened gingiva (unrelated to use of ASMs).
  One infant developed gingival hyperplasia at age seven months (two weeks prior to the initiation of ASMs) that became severe after age two years. His gingivae were so large that they protruded from his mouth, pressed his tongue to the pharynx, and covered his teeth. Because of difficulty with eating and breathing, he underwent full mouth gingivectomy twice, once at age four years and again at age six years. Histologic findings were gingival fibrous hyperplasia with mucoid depositions [Kondoh et al 2001]. Similar microscopic histologic findings were noted on postmortem examination in a four-day-old infant [Acuna-Hidalgo et al 2017].
• Neurobehavioral manifestations. To date, extensive information on behavior is not available. Although sleep disturbances and extensive periods of crying and irritability have been reported, additional evaluation is warranted for an underlying cause such as urinary tract infection and development of hydrocephalus or sacrococcygeal tumor.
• Growth. Birth length and weight are often within normal limits.
• Prenatal findings. Pregnancy may be complicated by polyhydramnios. Fetal ultrasound examination may reveal other findings such as hydronephrosis, ambiguous genitalia, cardiac defects, overlapping fingers, and/or a typical facial appearance.

Prognosis. The shortened life span of children with SGS may be correlated with the number and severity of the features present. While death mainly results from pneumonia (also after aspiration), other reported causes of death in early infancy include sepsis, lung hypoplasia, intractable epilepsy, and sudden cardiac arrest.

Genotype-Phenotype Correlations

Pathogenic variants in SETBP1 are now known to be associated with several phenotypes depending on their location and functional effects.

• Classic SGS is associated with pathogenic gain-of-function SETBP1 variants within the mutational hot spot (i.e., a 12-base-pair region in exon 4 encoding a canonical degron). These pathogenic variants are within amino acid residues 868-871 (p.Asp868Ala/Asn/Tyr, p.Ser869Gly/Asn/Arg, p.Gly870Cys/Asp/Ser, p.Ile871Ser/Thr). See Table 8.
• Atypical SGS is associated with pathogenic missense SETBP1 variants near – but not within – the mutational hot spot. The specific amino acid change is also thought to influence the resulting clinical phenotype. However, clear genotype-phenotype relationships have not been established at this time, and further research is needed to understand the molecular pathogenesis and clinical consequences of these pathogenic missense variants. For a summary of case reports and pathogenic reported missense variants, click here (xls).

Prevalence

To date, more than 50 individuals have been reported in the medical literature with molecularly confirmed classic SGS; more than 40 additional individuals were reported with the clinical diagnosis of classic SGS before SETBP1 pathogenic variants were known to be causative (see Clinical Description).

To date, five individuals with atypical SGS have been reported. For a summary of case reports and reported pathogenic missense variants in SETBP1, click here (xls).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with classic or atypical SGS, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment of Manifestations

There is no cure for classic or atypical Schinzel-Giedion syndrome. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This 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 (see Table 6).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

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 scarring from recurrent pyelonephritis and structural renal anomalies.

Evaluation of Relatives at Risk

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

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

Classic and atypical Schinzel-Giedion syndrome (SGS) are autosomal dominant disorders typically caused by a de novo SETBP1 pathogenic variant.

Risk to Family Members

Parents of a proband

• Most probands reported to date with classic or atypical SGS have the disorder as the result of 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 [Schinzel & Giedion 1978, Antich et al 1995]. 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) [Leonardi et al 2020].
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.

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 molecular diagnosis has been established in proband and the SETBP1 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Schinzel & Giedion 1978, Antich et al 1995].
• If the parents have not been tested for the SETBP1 pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SGS because of the possibility of parental germline mosaicism and, in atypical SGS, the possibility of incomplete penetrance or variable expressivity. (Transmission of an SETBP1 pathogenic variant from an unaffected parent to a child with atypical SGS has been reported in one family [Leonardi et al 2020].)

Offspring of a proband. Individuals with classic SGS are not known to reproduce.

Other family members. Given that most probands with a known heterozygous SGS-related SETBP1 pathogenic variant reported to date have the disorder as the result of a de novo pathogenic variant, the risk to other family members is presumed to be low.

Related Genetic Counseling Issues

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 parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the SETBP1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Although risk to future pregnancies is presumed to be low as the proband most likely has a de novo SETBP1 pathogenic variant, there is a slightly increased recurrence risk to sibs based on the possibility of parental germline mosaicism and, in atypical SGS, the possibility of incomplete penetrance or variable expressivity [Schinzel & Giedion 1978, Antich et al 1995, Leonardi et al 2020]. Given this risk, prenatal and preimplantation genetic testing may be considered.

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

SETBP1 encodes SET-binding protein (SEB), which binds the SET nuclear oncogene that is involved in DNA replication. Although the function of SEB is not yet fully understood, the protein is known to be involved in cell proliferation, neuronal migration, and neurogenesis [Acuna-Hidalgo et al 2017].

Classic Schinzel-Giedion syndrome (SGS) is caused by pathogenic heterozygous gain-of-function variants within a mutational hot spot of SETBP. This mutational hot spot is comprised of a 12-base-pair region within exon 4 encoding for amino acid residues 868 to 871 within the SKI domain. These four residues are part of a canonical degron sequence recognized by ubiquitin E3 ligases and are important for regulating protein degradation. In the presence of these pathogenic variants, the degradation "machinery" of the cell cannot bind to the protein efficiently. Therefore, less protein is degraded, which essentially results in overproduction of SEB.

Atypical SGS is caused by other pathogenic SETBP1 missense variants located near – but not within – the mutational hot spot and are associated with phenotypes with considerable clinical overlap with classic SGS.

Notably, other SETBP1 pathogenic missense variants either close to or further away from the mutational hot spot may be associated with a broad spectrum of phenotypes with insufficient clinical overlap with either SGS or SETBP1 haploinsufficiency disorder and are therefore considered to be associated with "SETBP1-related disorders" (see Genetically Related Disorders). These variants are expected to have heterogeneous functional effects (independent of SEB overabundance), including impaired ubiquitination, DNA binding, and transcription. Knowledge regarding associated phenotypes, as well as the spectrum of severity (including for classic and atypical SGS syndrome-associated pathogenic variants) is expected to continue to evolve as more variants are identified.

Mechanism of disease causation. Gain of function

Author Notes

Dr Bregje van Bon is involved in clinical follow up of individuals with SETBP1-related disorders. She would be happy to communicate with persons who have any questions regarding diagnosis of SETBP1 related disorders or other considerations.

Acknowledgments

The authors would like to thank all individuals with SGS, their families, and the Schinzel-Giedion Syndrome Foundation for sharing their medical and personal stories at the clinic and during live and online international meetings. They are the true experts, and we have been able write this GeneReview chapter based on their knowledge.

Revision History

• 7 March 2024 (bp) Review posted live
• 9 August 2023 (bvb) Original submission

Literature Cited

• Acuna-Hidalgo R, Deriziotis P, Steehouwer M, Gilissen C, Graham SA, van Dam S, Hoover-Fong J, Telegrafi AB, Destree A, Smigiel R, Lambie LA, Kayserili H, Altunoglu U, Lapi E, Uzielli ML, Aracena M, Nur BG, Mihci E, Moreira LM, Borges Ferreira V, Horovitz DD, da Rocha KM, Jezela-Stanek A, Brooks AS, Reutter H, Cohen JS, Fatemi A, Smitka M, Grebe TA, Di Donato N, Deshpande C, Vandersteen A, Marques Lourenco C, Dufke A, Rossier E, Andre G, Baumer A, Spencer C, McGaughran J, Franke L, Veltman JA, De Vries BB, Schinzel A, Fisher SE, Hoischen A, van Bon BW. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies. PLoS Genet. 2017;13:e1006683. [PMC free article: PMC5386295] [PubMed: 28346496]
• Antich J, Manzanares R, Camarasa F, Krauel X, Vila J, Cusi V. Schinzel-Giedion syndrome: report of two sibs. Am J Med Genet. 1995;59:96-9. [PubMed: 8849020]
• Bulut O, Ince Z, Altunoglu U, Yildirim S, Coban A. Schinzel-Giedion syndrome with congenital megacalycosis in a Turkish patient: report of SETBP1 mutation and literature review of the clinical features. Case Rep Genet. 2017;2017:3740524. [PMC free article: PMC5733194] [PubMed: 29333303]
• Carvalho E, Honjo R, Magalhaes M, Yamamoto G, Rocha K, Naslavsky M, Zatz M, Passos-Bueno MR, Kim C, Bertola D. Schinzel-Giedion syndrome in two Brazilian patients: Report of a novel mutation in SETBP1 and literature review of the clinical features. Am J Med Genet A. 2015;167A:1039-46. [PubMed: 25663181]
• Herenger Y, Stoetzel C, Schaefer E, Scheidecker S, Maniere MC, Pelletier V, Alembik Y, Christmann D, Clavert JM, Terzic J, Fischbach M, De Saint Martin A, Dollfus H. Long term follow up of two independent patients with Schinzel-Giedion carrying SETBP1 mutations. Eur J Med Genet. 2015;58:479-87. [PubMed: 26188272]
• Hishimura N, Watari M, Ohata H, Fuseya N, Wakiguchi S, Tokutomi T, Okuhara K, Takahashi N, Iizuka S, Yamamoto H, Mishima T, Fujieda S, Kobayashi R, Cho K, Kuroda Y, Kurosawa K, Tonoki H. Genetic and prenatal findings in two Japanese patients with Schinzel-Giedion syndrome. Clin Case Rep. 2016;5:5-8. [PMC free article: PMC5224771] [PubMed: 28096980]
• Hoischen A, van Bon BW, Gilissen C, Arts P, van Lier B, Steehouwer M, de Vries P, de Reuver R, Wieskamp N, Mortier G. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nature Genet. 2010;42:483-5. [PubMed: 20436468]
• Ko JM, Lim BC, Kim KJ, Hwang YS, Ryu HW, Lee JH, Kim JS, Chae JH. Distinct neurological features in a patient with Schinzel-Giedion syndrome caused by a recurrent SETBP1 mutation. Childs Nerv Syst. 2013;29:525-9. [PubMed: 23400866]
• Kondoh T, Kamimura N, Tsuru A, Matsumoto T, Matsuzaka T, Moriuchi H. A case of Schinzel-Giedion syndrome complicated with progressive severe gingival hyperplasia and progressive brain atrophy. Pediatr Int. 2001;43:181-4. [PubMed: 11285076]
• Lehman AM, McFadden D, Pugash D, Sangha K, Gibson WT, Patel MS. Schinzel-Giedion syndrome: report of splenopancreatic fusion and proposed diagnostic criteria. Am J Med Genet A. 2008;146A:1299-306. [PubMed: 18398855]
• Leonardi E, Bettella E, Pelizza MF, Aspromonte MC, Polli R, Boniver C, Sartori S, Milani D, Murgia A. Identification of SETBP1 mutations by gene panel sequencing in individuals with intellectual disability or with "developmental and epileptic encephalopathy". Front Neurol. 2020;11:593446. [PMC free article: PMC7772201] [PubMed: 33391157]
• Leone MP, Palumbo P, Palumbo O, Di Muro E, Chetta M, Laforgia N, Resta N, Stella A, Castellana S, Mazza T, Castori M, Carella M, Bukvic N. The recurrent SETBP1 c.2608G > A, p.(Gly870Ser) variant in a patient with Schinzel-Giedion syndrome: an illustrative case of the utility of whole exome sequencing in a critically ill neonate. Ital J Pediatr. 2020;46:74. [PMC free article: PMC7254667] [PubMed: 32460883]
• Lestner JM, Chong WK, Offiiah A, Kefas J, Vandersteen AM. Unusual neuroradiological features in Schinzel-Giedion syndrome: a novel case. Clin Dysmorphol. 2012;21:152-4. [PubMed: 22473152]
• López-González V, Domingo-Jiménez MR, Burglen L, Ballesta-Martínez MJ, Whalen S, Piñero-Fernández JA, Guillén-Navarro E. [Schinzel-Giedion syndrome: a new mutation in SETBP1]. An Pediatr (Barc). 2015;82:e12-6. [PubMed: 25082129]
• Makishima H, Yoshida K, Nguyen N, Przychodzen B, Sanada M, Okuno Y, Ng KP, Gudmundsson KO, Vishwakarma BA, Jerez A, Gomez-Segui I, Takahashi M, Shiraishi Y, Nagata Y, Guinta K, Mori H, Sekeres MA, Chiba K, Tanaka H, Muramatsu H, Sakaguchi H, Paquette RL, McDevitt MA, Kojima S, Saunthararajah Y, Miyano S, Shih LY, Du Y, Ogawa S, Maciejewski JP. Somatic SETBP1 mutations in myeloid malignancies. Nat Genet. 2013;45:942-6. [PMC free article: PMC3729750] [PubMed: 23832012]
• Matsumoto F, Tohda A, Shimada K, Okamoto N. Malignant retroperitoneal tumor arising in a multicystic dysplastic kidney of a girl with Schinzel-Giedion syndrome. Int J Urol. 2005;12:1061-2. [PubMed: 16409612]
• Minn D, Christmann D, De Saint-Martin A, Alembik Y, Eliot M, Mack G, Fischbach M, Flament J, Veillon F, Dollfus H. Further clinical and sensorial delineation of Schinzel-Giedion syndrome: report of two cases. Am J Med Genet. 2002;109:211-7. [PubMed: 11977181]
• Miyake F, Kuroda Y, Naruto T, Ohashi I, Takano K, Kurosawa K. West syndrome in a patient with Schinzel-Giedion syndrome. J Child Neurol. 2015;30:932-6. [PubMed: 25028416]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Santos H, Cordeiro I, Medeira A, Mendonça E, Antunes NL, Rosa FC. Schinzel-Giedion syndrome. A patient with hypothyroidism and diabetes insipidus. Genet Couns. 1994;5:187-9. [PubMed: 7917131]
• Schinzel A, Giedion A. A syndrome of severe midface retraction, multiple skull anomalies, clubfeet, and cardiac and renal malformations in sibs. Am J Med Genet. 1978;1:361-75. [PubMed: 665725]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197-207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Sullivan JA, Stong N, Baugh EH, McDonald MT, Takeuchi A, Shashi V. A pathogenic variant in the SETBP1 hotspot results in a forme-fruste Schinzel-Giedion syndrome. Am J Med Genet A. 2020;182:1947-51. [PubMed: 32445275]
• Suphapeetiporn K, Srichomthong C, Shotelersuk V. SETBP1 mutations in two Thai patients with Schinzel-Giedion syndrome. Clin Genet. 2011;79:391-3. [PubMed: 21371013]
• Takeuchi A, Okamoto N, Fujinaga S, Morita H, Shimizu J, Akiyama T, Ninomiya S, Takanashi J, Kubo T. Progressive brain atrophy in Schinzel-Giedion syndrome with a SETBP1 mutation. Eur J Med Genet. 2015;58:369-71. [PubMed: 26096993]
• Volk A, Conboy E, Wical B, Patterson M, Kirmani S. Whole-exome sequencing in the clinic: lessons from six consecutive cases from the clinician's perspective. Mol Syndromol. 2015;6:23-31. [PMC free article: PMC4369115] [PubMed: 25852444]
• Yang H, Liu Z, Chen D, Lin W, Wang L, Chen T, Wang R, Yan X. Detection of a novel SETBP1 variant in a Chinese neonate with Schinzel-Giedion syndrome. Front Pediatr. 2022;10:920741. [PMC free article: PMC9488805] [PubMed: 36147799]