Shprintzen-Goldberg Craniosynostosis Syndrome

A number sign (#) is used with this entry because of evidence that Shprintzen-Goldberg craniosynostosis syndrome (SGS) is caused by heterozygous mutation in the SKI gene (164780) on chromosome 1p36.

Description

Shprintzen-Goldberg syndrome is a disorder comprising craniosynostosis, a marfanoid habitus, and skeletal, neurologic, cardiovascular, and connective tissue anomalies. There appears to be a characteristic facies involving hypertelorism, downslanting palpebral fissures, high-arched palate, micrognathia, and low-set posteriorly rotated ears. Other commonly reported manifestations include hypotonia, developmental delay, and inguinal or umbilical hernia; the most common skeletal manifestations are arachnodactyly, pectus deformity, camptodactyly, scoliosis, and joint hypermobility (summary by Robinson et al., 2005).

There is considerable phenotypic overlap between SGS and Marfan syndrome (MFS; 154700) and Loeys-Dietz syndrome (LDS; see 609192): SGS includes virtually all of the craniofacial, skeletal, skin, and cardiovascular manifestations of MFS and LDS, with the additional findings of mental retardation and severe skeletal muscle hypotonia (summary by Doyle et al., 2012).

Clinical Features

In 2 unrelated boys, Shprintzen and Goldberg (1982) described a 'new' syndrome of craniosynostosis associated with severe exophthalmos, maxillary and mandibular hypoplasia, soft tissue hypertrophy of the palatal shelves, low-set ears with soft and pliable auricles, multiple abdominal hernias, arachnodactyly, and camptodactyly. Functional disorders included infantile hypotonia, developmental delay, mental retardation, and obstructive apnea. The marked soft tissue of the palatal shelves created a 'pseudocleft' of the palate. Pectus carinatum was present in one of the boys and pectus excavatum in the other.

Gorlin et al. (1990) discussed Shprintzen-Goldberg syndrome (SGS) and related syndromes.

Ades et al. (1995) delineated the distinct skeletal abnormalities of the Shprintzen-Goldberg syndrome on the basis of 4 affected girls. Three of them showed bowing of long bones (with a variable degree of progression over time), flare of the metaphyses, a large anterior fontanel with persistent patency into the second to fourth years of life, 13 pairs of ribs, distinct vertebral abnormalities that were absent neonatally but evolved by the second year of life, and progressive osteopenia. Communicating hydrocephalus was present in all 4 cases. Arachnodactyly was illustrated as well as a superior folding of the helix of the ear, reminiscent of that in congenital contractural arachnodactyly (121050). Two of the patients were monozygotic twin girls and another sister was case 4. Apart from this family, all known cases were sporadic. The 3 sibs were products of a nonconsanguineous union, and there had been no previous documented instance of parental consanguinity. Ades et al. (1995) concluded that SGS is probably a generalized connective tissue dysplasia. Saal et al. (1995) reported another female patient with the craniosynostosis and marfanoid phenotype. The disorder was detected prenatally by the presence of a cloverleaf skull. She also had choanal atresia and stenosis. One of the patients reported by Ades et al. (1995) had intestinal malrotation and anteriorly placed anus. Shah et al. (1996) reported an Indian patient with the association of Marfan syndrome (with a dilated aortic root and atlantoaxial dislocation) and the fusion of coronal and sagittal skull sutures.

Hassed et al. (1997) described a boy with Shprintzen-Goldberg syndrome, presumably the twelfth patient to be reported. In addition to the commonly described anomalies of individuals with SGS, this patient also had cranial asymmetry, hypotonia, osteopenia, and hydrocephalus.

Greally et al. (1998) presented 4 new patients with SGS and reviewed 1 of the patients in the original report of Shprintzen and Goldberg (1982). They concluded that radiologic investigations are particularly helpful in differentiating SGS from other syndromes with craniosynostosis and marfanoid habitus. Abnormality of the first and second cervical vertebrae, hydrocephalus, dilatation of the lateral ventricles, and a Chiari-I malformation of the brain were found only in the patients with Shprintzen-Goldberg syndrome. Pectus excavatum and striking arachnodactyly were pictured.

Stoll (2002) reported a 24-year follow-up of a patient with SGS. Dysmorphic features were noted in infancy and became more pronounced over time. These included brachycephaly, posteriorly rotated floppy ears, shallow orbits, hypertelorism, midfacial hypoplasia, a narrow palate, sagittal synostosis, arachnodactyly, camptodactyly, pectus excavatum, scoliosis, bilateral inguinal and crural hernias, fragile skin, and lack of subcutaneous fat. Pectus excavatum was severe and scoliosis worsened during adolescence. Foot deformities included hallux varus, metatarsophalangeal dislocation, hammertoes and tarsometatarsal dislocation. There was also bilateral dislocation of the radial heads. Myopia was present and worsened over time. Height and weight were reduced initially but final adult height was normal. Puberty was delayed. Despite initial psychomotor developmental delay, the patient had no resulting mental retardation. No mutation was found in the gene encoding fibrillin-1.

Loeys et al. (2005) compared the clinical features of their series of cases with the Loeys-Dietz syndrome with that of SGS as presented by Greally et al. (1998) and with Marfan syndrome. Cleft palate/bifid uvula was present in 100% of cases of LDS, in none of the MFS patients, and in 1 of 15 SGS cases. Aortic root aneurysm was present in 16 of 16 cases of LDS and 2 of 15 of SGS. Arterial tortuosity was present in 11 of 11 LDS cases and was not associated with the other 2 conditions. Blue sclerae were present in 8 of 13 LDS patients and were not associated with the other 2 conditions. Ectopia lentis was not present in any of the 16 cases of LDS. Patent ductus arteriosus and atrial septal defect were present in 54% and 31%, respectively, of LDS cases but were not associated with the other 2 conditions.

Robinson et al. (2005) reported 13 unrelated patients and 1 sib with SGS and compared their clinical findings with those of 23 previously reported individuals. They suggested that there is a characteristic facial appearance, with more than two-thirds of all individuals having hypertelorism, downslanting palpebral fissures, a high-arched palate, micrognathia, and apparently low-set and posteriorly rotated ears.

The related disorders SGS and Furlong syndrome (LDS; see 609192) feature marfanoid habitus and craniosynostosis. Megarbane and Hokayem (1998) suggested dividing craniosynostosis with marfanoid habitus into 2 types: type 1, with mental retardation (SGS), and type 2, with normal intelligence and aortic root anomalies (Furlong syndrome).

Ades et al. (2006) questioned the diagnosis of SGS in one of the patients of Greally et al. (1998) and in the patient of Stoll (2002).

Molecular Genetics

Doyle et al. (2012) performed whole-exome sequencing in a woman with Shprintzen-Goldberg syndrome and her unaffected parents and identified only 1 variant, a de novo heterozygous missense mutation in the SKI gene (G116E; 164780.0001). The mutation was not present in the unaffected parents or in SNP databases. Subsequent sequencing of SKI in 11 more sporadic cases of SGS revealed heterozygous variants in 9 of the patients, including 7 missense mutations and a 9-bp deletion (see, e.g., 164780.0002-164780.0005). The mutations were not found in SNP databases or in the unaffected parents in the 5 cases in which parental DNA was available. All 10 mutation-positive patients had skeletal muscle hypotonia and developmental delay; 8 of the 10 also had aortic root dilation, 1 had arterial tortuosity, and 2 had splenic artery aneurysm, which spontaneously ruptured in 1 patient. Doyle et al. (2012) stated that despite near-complete phenotypic overlap between Loeys-Dietz syndrome and SGS, the aneurysm phenotype in SGS is less penetrant, less diffuse (generally restricted to the aortic root), and less severe than that seen in LDS. Cultured dermal fibroblasts from mutation-positive SGS patients showed enhanced activation of TGF-beta (TGFB1; 190180) signaling cascades and higher expression of TGF-beta-responsive genes relative to control cells. Doyle et al. (2012) concluded that increased TBF-beta signaling is the mechanism underlying SGS and that high signaling contributes to multiple syndromic presentations of aortic aneurysm.

In 18 of 19 patients with characteristic features of SGS who were negative for mutation in the FBN1 (134797), TGFBR1 (190181), and TGFBR2 (190182) genes, including 5 affected individuals over 3 generations in 1 family and another family in which 3 sibs were affected, Carmignac et al. (2012) identified heterozygosity for 2 different in-frame deletions and 10 missense mutations in the SKI gene (see, e.g., 164780.0002, 164780.0004, 164780.0005, and 164780.0007-164780.0010). No SKI mutations were found in a cohort of 11 patients with other marfanoid craniosynostosis syndromes. Carmignac et al. (2012) noted that 3 of the 18 patients with SKI mutations had aortic dilation, 1 of whom also had vertebrobasilar and internal carotid tortuosity and a dilated pulmonary artery root, further highlighting the overlap between SGS and LDS; however, all of the patients with SKI mutations had intellectual disability, supporting the hypothesis that they are distinct syndromes.

In patients with Marfan syndrome (154700) who also had features of Shprintzen-Goldberg syndrome, including craniosynostosis and mental retardation, Sood et al. (1996) and Kosaki et al. (2006) identified heterozygous mutations in the FBN1 gene (134797.0022 and 134797.0045). Doyle et al. (2012) stated that it may be significant that both of the identified mutations reside in the same EGF-like domain of fibrillin.

Schepers et al. (2015) analyzed the SKI gene in 19 patients with clinically suspected SGS and identified 8 recurrent and 3 novel mutations in 11 patients (see, e.g., 164780.0002-164780.0004, 164780.0007; 164780.0010). The authors stated that their findings, in combination with previously reported data, clearly show a mutational hotspot in the SKI gene, with 24 (73%) of 33 unrelated patients having mutations within a stretch of 5 residues (from ser31 to pro35). Schepers et al. (2015) noted that, in contrast to the SGS patients reported by Doyle et al. (2012), only 2 of the patients in their series presented with aortic root dilation.

Animal Model

Doyle et al. (2012) generated zebrafish with morpholino-based knockdown of the 2 paralogs of mammalian SKI (skia and skib), and observed mutant embryos with marked craniofacial cartilage deficits, including shortened and flat Meckel cartilage, irregular lengths of palatoquadrates, shortened ceratohyales, and depleted ceratobranchial arches. These deficits manifested in larval fish as maxillary hypoplasia, malformed ethmoid plate, micrognathia and microcephaly, and were frequently accompanied by ocular hypertelorism and spinal malformation. In addition, the skia- and skib-morphant embryos showed severe cardiac anomalies, characterized by partial to complete failure in cardiac looping and malformations of the outflow tract. Doyle et al. (2012) noted that in comparison to Ski-null mice, the zebrafish morphants more closely recapitulated the human SGS craniofacial phenotype.