Definition

Schinzel-Giedion syndrome (SGS, OMIM #269150) is a genetic disease caused by mutations in the SETBP1 gene. It is characterized by severe developmental delays, characteristic facies, and multiple congenital anomalies, particularly of a skeletal, urogenital, renal, and cardiac nature. In addition, there is also a predisposition to embryonic tumors, hepatoblastomas, and sacrococcygeal germ cell tumors. Patients usually die within the first decade of life.

Key Data

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Synonym Schinzel-Giedion midface retraction syndrome
Gene SETBP1
Gene product SET-binding protein-1
Function DNA replication
Heredity Autosomal dominant, but generally de novo mutations
Prevalence <1 : 1.000.000
Genotype-phenotype correlation Unknown
Penetrance Unknown
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Diagnosis

Clinical Diagnostic Criteria

Obligatory criteria:

  • Developmental delays (except in newborns)

  • Characteristic facies:

    • Prominent forehead
    • Midface retraction
    • Short upturned nose

In addition, one of the following criteria:

  • Hydronephrosis

  • Two of the following typical skeletal malformations:

    • Sclerotic skull base
    • Broad supraoccipital-exocciptal synchondrosis
    • Increased cortical density or thickness
    • Wide ribs

Genetic Diagnostics

In addition to the clinical diagnosis, the diagnosis of “Schinzel-Giedion syndrome” is confirmed by the detection of a heterozygous germline mutation in the SETBP1 gene through sequence analysis or deletion/duplication analysis.

Differential Diagnoses

Chromosomal Aberrations:

  • 20p deletion

  • Tetrasomy 12p mosaicism (Pallister-Killian syndrome)

  • 9p deletion

  • Trisomy 9 mosaicism

Multiple Congenital Anomalies Syndromes:

  • Mowat-Wilson

  • Hypertelorism-hypospadias syndrome

  • CHARGE syndrome

  • Smith-Lemli-Opitz syndrome

Diseases with Midface Retraction:

  • Mucopolysaccharidosis

  • Gangliosidosis

  • Hypothyroidism

  • Chondrodysplasia punctata, rhizomelic type

  • Robinow syndrome

Clinical Presentation

Prenatal

Hydronephrosis may develop prenatally, usually occurring bilaterally and with varying presentations. In addition, there may also be polyhydramnios.

Craniofacial Malformation

The characteristic facies consist of midface hypoplasia and retraction (present in all patients), large anterior fontanels, a prominent bulging forehead, short upturned nose, ocular hypertelorism, a broad mouth with macroglossia, a short neck, low-lying ears with malformations, and hypertrichosis. The presentation of these different features varies between individuals.

Organ Manifestations

Hydronephrosis can be found in over 90% of patients, ranging from mild pyelectasia to severe hydronephrosis.
The majority of patients (76%) exhibit anomalies, which generally present as hypoplasia of the genitals and hypospadias.
Cardiac anomalies can be found in nearly half of the patients and may involve valvular dysplasia or stenosis, hypoplastic ventricles, septal defects, or persistent ductus arteriosus.

Approximately one quarter of patients suffer from choanal atresia or stenosis.

Neurological Abnormalities

Severe developmental delays can be identified in the majority of patients, whereby cramp seizures are frequently described (in around 70%) that are usually difficult to interrupt. Moreover, visual and hearing impairment may occur as well. Cranial imaging may reveal ventriculomegaly, an underdeveloped corpus callosum, cortical atrophy, and choroid plexus cysts. Approximately half of the patients exhibit a failure to thrive.

Tumors

Malignant tumors have been described in a few patients, namely sacrococcygeal germ cell tumors, sacrococcygeal primitive neuroectodermal tumors, one extradural ependymoma, one hepatoblastoma, and one malignant retroperitoneal tumor. While the risk of developing cancers has not yet been quantitated, it appears to be elevated based on the cumulative number of cancer cases in relation to the number of patients identified to date (around 10 tumors in 70 patients, indicating that the risk of cancer may be between 10% and 15%).

Manifestations in the Extremities

Among the commonly observed abnormalities of the extremities are mesomelic brachymeria, hyperconvex nails, valgus or varus foot positions, and simian crease.

Skeletal Abnormalities

X-rays of those affected often show wide ribs, a thickened, dense cortex of the long bones of the extremities, and hypoplastic distal phalanges. In addition, a sclerotic and shortened skull base and broad occipital synchondrosis is commonly described as well.

Therapeutic Considerations

In light of the large number of potential manifestations, treatment should always be symptom-oriented and interdisciplinary, with the involvement of the corresponding specialist disciplines.

Surveillance Recommendations

Surveillance Recommendations

Patients and their families should be informed of the presumed high risk of cancer of between 10-15%.

During basic diagnostics, the risk of congenital tumors should always be borne in mind. With regard to skeletal, neurological, and renal abnormalities, such diagnostics should include spinal, abdominal, and pelvic imaging.

In patients with severe symptoms, determining the tumor markers AFP and β-HCG may well be helpful in addition to a basic blood analysis.

For milder progressions, regularly determining AFP and β-HCG and conducting regular abdominal and pelvic ultrasounds should be considered as well.

Additional Information

Open Clinical Trials / Registries

There are currently no open clinical trials/registries for patients with Schinzel-Giedion syndrome that we can recommend to you for more information.

Support Groups

Unfortunately, we are as yet unaware of any existing support groups for patients with Schinzel-Giedion syndrome. We will add new information as it becomes available.