Schinzel-Giedion Midface Retraction Syndrome

A number sign (#) is used with this entry because of evidence that Schinzel-Giedion midface retraction syndrome is caused by heterozygous de novo mutation in the SETBP1 gene (611060) on chromosome 18q12.

Description

Schinzel-Giedion syndrome is a highly recognizable syndrome characterized by severe mental retardation, distinctive facial features, and multiple congenital malformations including skeletal abnormalities, genitourinary and renal malformations, and cardiac defects, as well as a higher-than-normal prevalence of tumors, notably neuroepithelial neoplasia (summary by Hoischen et al., 2010).

Clinical Features

Schinzel and Giedion (1978) described a unique syndrome in brother and sister, who lived 24 hours and 16 months, respectively. Severe midface retraction, multiple skull anomalies (short and sclerotic base, multiple wormian bones, wide cranial sutures and fontanels), congenital heart defect, hydronephrosis, clubfeet, and hypertrichosis were features. Long tubular bones also showed increased density. Another syndrome carries Schinzel's name (181450), and Giedion's is combined with Langer's for a disorder resembling the trichorhinophalangeal syndrome (150230). Despite these possibilities for confusion, I have assigned the above designation for want of a better one (VAM).

Donnai and Harris (1979) reported a case in which multiple telangiectases were observed over the nose and cheeks. By personal communication and observation, Schinzel (1982) was aware of a total of 8 other unreported cases, all sporadic, including at least 2 offspring of consanguineous parents.

Al-Gazali et al. (1988) reported 3 cases. Hypoplasia of dermal ridges and genital anomalies were mentioned as abnormalities. The skeletal abnormalities also included broad ribs and hypoplasia of the distal phalanges. Two of the 7 children reported in the literature died in the neonatal period, and the remainder developed intractable epilepsy and spasticity along with profound growth and developmental retardation.

Al-Gazali et al. (1990) reviewed 5 previously reported cases and 5 new cases. They stated that consanguinity in fact had not been observed, but that 2 sibs of unlike sex are known. Thus, a dominant disorder with gonadal mosaicism in one parent or an unbalanced structural chromosome abnormality that went undetected by present methods cannot be excluded.

Maclennan et al. (1991) described increasing ventriculomegaly, intraventricular bands, and subependymal pseudocysts in an affected infant born prematurely who died at the age of 9 weeks.

Robin et al. (1993) described malignant sacrococcygeal teratoma discovered soon after birth. They pointed out that Burck (1982) described hepatoblastoma in this disorder and suggested that embryonal malignancy may be a common complication. Labrune et al. (1994) added 3 new cases to the 13 previously reported.

Rodriguez et al. (1994) reported the third example of a postmortem study. In addition to having the major manifestations of the syndrome, the 11-month-old boy with SGS had a primitive neuroectodermal tumor in the lumbosacral region, bilateral syndactyly of the hands and feet, and brain anomalies. Rodriguez et al. (1994) commented that of 19 SGS patients reported, 4 had syndactyly and 3 had embryonal tumors; the 3 published necropsy studies showed brain anomalies. They noted that the only familial cases were the affected sibs in the initial report by Schinzel and Giedion (1978). Antich et al. (1995) reported the cases of a brother and sister. The sister had a malignant sacrococcygeal teratoma (the third case of malignancy in Schinzel-Giedion syndrome). The brother died shortly after birth. McPherson et al. (1998) reported a fourth patient with Schinzel-Giedion syndrome and a sacrococcygeal tumor (the previous cases being those of Robin et al. (1993), Rodriguez et al. (1994), and Antich et al. (1995)).

Santos et al. (1994) described a girl with characteristic manifestations of SGS (including typical face, skeletal abnormalities, and hydronephrosis) who also had hypothyroidism and diabetes insipidus. The TSH value in her newborn period was normal. MRI of her brain at 9 months of age showed malformation of the posterior fossa and arachnoid cysts in both temporal regions and in the left cerebellar hemisphere. The brainstem seemed to be pushed backwards by an anterior cyst, and the pituitary stalk was stretched. Santos et al. (1994) suggested that hypothyroidism and diabetes insipidus were secondary to these central defects.

Okamoto et al. (1995) reported a patient they claimed to be the twenty-first in the literature and the first reported instance of the syndrome in an Oriental patient.

Elliott et al. (1996) described a male infant who, in addition to typical manifestations (characteristic face, choanal stenosis, tricuspid regurgitation, hypospadias), had seizures, hearing loss, camptodactyly, and dysplastic sternum. Autopsy disclosed small brain with diminution of white matter (but no evidence of any brain storage), hypoplastic corpus callosum, steatosis of liver, and lipid vacuolization of the zona fasciculata of the adrenals.

Shah et al. (1999) reported a case of Schinzel-Giedion syndrome with serial cranial MRI studies consistent with a progressive neurodegenerative process affecting both gray and white matter. Although the authors thought that these studies, along with the coarse facial features, skeletal abnormality, and progressive neurologic deterioration, suggested a storage or metabolic neurodegenerative process, the results of their metabolic studies were normal.

Minn et al. (2002) described 2 unrelated children born of nonconsanguineous parents with SGS and identical clinical findings: megacalycosis and progressive neurodegeneration with infantile spasms and hypsarrhythmic activity. Alacrimia and corneal hypoesthesia were observed. Computed tomography of the temporal bone showed a 'tuning-fork' malformation of the stapes in both children. Bilateral megacalycosis, as opposed to hydronephrosis, is a nonobstructive dilatation of the calyces, assumed to be the result of an underdevelopment of the renal medullary pyramids. Megaureter is a common associated feature and was present in 1 of the cases of Minn et al. (2002). Megacalycosis had been previously observed by Herman et al. (1993) and Rittinger et al. (1999).

Like Minn et al. (2002), Manouvrier-Hanu (2003) described alacrima with corneal hypoesthesia as a valuable diagnostic sign in Schinzel-Giedion syndrome.

Lehman et al. (2008) described what they stated was the forty-sixth reported patient with Schinzel-Giedion syndrome, a male infant born of nonconsanguineous Persian parents, in whom the previously unreported feature of splenopancreatic fusion was found on autopsy.

Suphapeetiporn et al. (2011) reported 2 male Thai patients with Schinzel-Giedion syndrome who displayed some features not previously reported in the disorder, including very short epiglottis, vocal cord paralysis, radioulnar synostosis, and possible hypothyroidism.

Diagnosis

Lehman et al. (2008) reviewed previously reported cases and proposed diagnostic criteria for the syndrome consisting of a mandatory facial phenotype involving prominent forehead, midface retraction, and short, upturned nose; developmental delay (excepting neonates); and either hydronephrosis or 2 of the 4 typical skeletal malformations, i.e., sclerotic skull base, wide occipital synchondrosis, increased cortical density or thickness, or broad ribs.

Mapping

Hoischen et al. (2010) sequenced the 37-Mb exomes of 4 unrelated individuals with Schinzel-Giedion syndrome and identified 12 genes for which all 4 patients carried variants. Only 2 genes, CTBP2 (602619) and SETBP1 (611060), showed variants at different genomic positions, suggesting that these represented causative variants rather than simply unidentified SNPs. The CTBP2 gene was excluded from further analysis because it contained numerous variants found during different in-house exome sequencing experiments, considered possibly due to highly homologous sequences from other genomic loci.

Molecular Genetics

In 4 unrelated individuals with Schinzel-Giedion syndrome, Hoischen et al. (2010) sequenced the candidate gene SETBP1 and identified de novo heterozygous mutations in all 4 individuals; using Sanger sequencing, they identified de novo heterozygous SETBP1 mutations in 8 of 9 additional individuals with Schinzel-Giedion syndrome (611060.0001-611060.0005). None of the mutations were found in available parents or in 188 control chromosomes. All 13 patients fulfilled the diagnostic criteria proposed by Lehman et al. (2008) and were of European descent from various parts of the world, including 7 from Europe, 3 from New Zealand, 2 from Australia, and 1 from the United States.

In 2 unrelated Thai male infants who fulfilled the diagnostic criteria for Schinzel-Giedion syndrome, Suphapeetiporn et al. (2011) identified heterozygosity for the G870S mutation in the SETBP1 gene (611060.0005).