Marshall Syndrome

A number sign (#) is used with this entry because of evidence that Marshall syndrome (MRSHS) is caused by heterozygous mutation in the COL11A1 gene (120280) on chromosome 1p21.

Stickler syndrome type II (604841) is an allelic disorder with overlapping features.

Clinical Features

Marshall (1958) reported 4 generations of a family in which 7 members had (1) nasal defect and facies characteristic of anhidrotic ectodermal dysplasia; (2) congenital and juvenile cataracts; (3) myopia and fluid vitreous; (4) spontaneous, sudden maturation and absorption of congenital cataract; (5) luxation of cataract and (6) congenital hearing loss. Deficiency in sweating was minimal. The transmission was dominant.

Marshall (1958) emphasized the ectodermal abnormalities, including defects in sweating and dental structures in the family he reported, which had 7 affected members in 3 generations. Shanske et al. (1997) found reports of 7 subsequently reported families, seemingly with the same disorder; they added an eighth family with 6 affected individuals in 4 generations. The affected individuals had ectodermal dysplasia and ocular hypertelorism, features not shared by Stickler syndrome (see 108300), Wagner syndrome (143200), or Weissenbacher-Zweymuller syndrome (WZS; 184840), all of which are conditions often confused with Marshall syndrome. The proposita of the African American family had sparse scalp hair and sparse eyebrows and lashes, but her teeth, nails, and sweating were normal. Craniofacial surgery was performed for hypertelorism. Her 2 brothers were also affected and had craniofacial surgery.

Ruppert et al. (1970) described father and daughter with features like those in Marshall's family, namely saddle nose, myopia, and deafness and, in the father, cataracts. Cohen et al. (1971) described a father and 2 sons and 2 daughters with myopia, hyaloideoretinal degeneration, retinal detachment, flat face from maxillary hypoplasia, and in the father and 2 of his children, submucous cleft palate. Families that the authors felt had the same disorder also included those reported by Delaney et al. (1963) and Frandsen (1966). Retinal detachment with complicating cataract and cleft palate occurred in multiple members of a family reported by Delaney et al. (1963). Two brothers reported as Pierre Robin syndrome (see 261800) with eye complications by Smith and Stowe (1961) and by Smith (1969) probably had this condition or the Stickler syndrome.

Zellweger et al. (1974) considered Marshall syndrome a distinct entity. They provided a report of the third recorded family, the others being those of Marshall (1958) and Ruppert et al. (1970). Cohen (1974) wrote that 'it is time to put an end to the so-called Marshall syndrome.' Yet the book of which he was a co-author (Gorlin et al., 1976) listed and discussed it as a distinct entity. Cohen (1974) thought the reported families in fact had Stickler syndrome. O'Donnell et al. (1976) insisted that the Marshall syndrome is distinct from the Stickler syndrome because of the rarity of cleft palate in the former and of deafness in the latter. They found calcification of the falx cerebri and meninges in a case, as well as platyspondyly.

Winter et al. (1983) described families demonstrating nosologic overlap among Weissenbacher-Zweymuller syndrome, Stickler syndrome, and Marshall syndrome. Three unrelated children with neonatal radiologic characteristics of the Weissenbacher-Zweymuller syndrome, including small mandible, midface hypoplasia, cleft palate, and dumbbell-shaped femora, subsequently developed Marshall syndrome. The first patient was found at age 3 months to have high myopia, extensive vitreous detachments and thin peripheral retina, as well as moderate hearing loss. The second patient had a small VSD that closed spontaneously. He had nerve deafness but no eye abnormality was detected at age 2 years. The third patient had both sensorineural deafness and severe myopia. His father and 1 of 2 sisters were also affected. Winter et al. (1983) interpreted the findings in the father of patient 3 as consistent with Stickler syndrome and concluded that Marshall, WZS, and Stickler syndromes are manifestations of the identical mutation. They also noted the phenotypic overlap with Nance-Insley syndrome (OSMEDB; 215150).

The distinctness of the Stickler and Marshall syndromes was strongly supported by the work of Ayme and Preus (1984) who surveyed published reports on the 2 syndromes. A set of 18 patients with clinical description, photographs, and radiographs was used to tabulate a list of 53 signs. Cluster analysis using these signs demonstrated 2 groups of patients. An index score based on the 20 most discriminating signs was applied to other reported patients with confirmation of the authors' diagnosis. Ayme and Preus (1984) concluded, therefore, that there is 'no objective reason to consider that these two syndromes are not separate dominant disorders with variable expressivity.' They suggested that the facies differ. Patients with the Marshall syndrome have a flat or retracted midface whereas those with the Stickler syndrome have a flat mala which is often erroneously described as a flat midface. Marshall syndrome patients have a thick calvaria, abnormal frontal sinuses, and intracranial calcifications. The eyeballs appear large, possibly because of a shallow orbit. Opitz and Lowry (1987) stated: 'We have the strong impression that the Marshall syndrome is different from the Stickler syndrome in spite of clinical overlap.'

Stratton et al. (1991) reported Marshall syndrome in mother and daughter; the daughter also had the Pierre Robin sequence. The mother was 147 cm tall. Profile photograph showed flat facies with short nose and upturned tip and nares. She wore bilateral hearing aids and had high-grade myopia. There was mild brachycephaly with an area of occipital cutis aplasia, which had been present since birth. Studies of the COL2A1 gene (120140) showed no gross rearrangement.

Griffith et al. (1998) described a large kindred with Marshall syndrome in which 9 affected members of the family, in 3 generations, were available for study. Features of Marshall syndrome included a markedly short nose with flat root, depression of the nasal bridge, anteverted nostrils, and retracted midface. Four of the affected persons had cleft palate and recurrent otitis media, which also were associated with Pierre Robin sequence in 1 individual. Four other affected individuals had bifid uvula. No dental anomalies were observed. Affected individuals had myopia and cataracts, which became apparent during the first decade of life and were located in subcapsular, cortical, nuclear, zonular, or anterior axial embryonic sites. Fluid vitreous humor was present in all affected individuals undergoing cataract surgery. Sensorineural hearing loss was noted as early as 3 years of age, with gradual progression to moderate or severe levels by late adulthood. Other features included short stature relative to unaffected family members and stocky build. Also observed was symptomatic osteoarthritis beginning in the fourth or fifth decades and affecting the knees and lumbosacral spine, as well as mild hypotrichosis and hypohidrosis in some affected family members. Radiologic findings included hypoplasia of the maxilla, nasal bones, and frontal sinuses, calvarial thickening and intracranial calcifications, and narrowed joint spaces, with osteophytic degeneration in the hips and knees.

Shanske et al. (1998) suggested that the family reported by Griffith et al. (1998) suffered from Stickler syndrome, not Marshall syndrome. Shanske et al. (1997) reported a family in which 6 members in 4 generations were affected with Marshall syndrome. From a review of the literature, they attempted to distinguish the Stickler and Marshall syndromes. In both disorders, ophthalmologic abnormalities including high myopia, as well as midfacial hypoplasia, micrognathia with or without palatal clefting, and nonspecific skeletal abnormalities have been reported. In spite of these overlaps, each of the disorders has distinctive features. Striking ocular hypertelorism and abnormalities of ectodermal derivatives had been reported only in Marshall syndrome. The phenotype described by Griffith et al. (1998) included only 'mild' orbital hypertelorism and no evidence of ectodermal derivative abnormalities. Shanske et al. (1998) suggested, therefore, that the family reported by Griffith et al. (1998) most likely did not have Marshall syndrome but had the subset of Stickler syndrome in families associated with COL11A1 mutations.

Warman et al. (1998) vigorously defended the diagnosis of Marshall syndrome in the family they reported (Griffith et al., 1998). They argued that a comparison of the principal findings reported by Marshall (1958) with the findings in their family revealed high concordance, whereas comparison with the patients reported by Shanske et al. (1997) showed low concordance. Marshall's patients and their patients all had congenital or juvenile cataracts and fluid vitreous; none of the patients described by Shanske et al. (1997) had these conditions. Marshall's patients and their patients all had significant hearing loss; none of the patients described by Shanske et al. (1997) had hearing loss. Marshall's patients had 'ample and normal hair,' as did their patients; the patients described by Shanske et al. (1997) all had 'sparse' hair or a 'paucity of hair.' Two of Marshall's patients were studied radiographically; each had nasal bones that were 'small, short, and far back of their normal position.' These patients also had 'prominence of the frontal bossae,' which served to 'accentuate the flatness or depression of the bridge of the nose,' and 'thickening of the outer table of the skull and absent frontal sinuses.' In their report (Griffith et al., 1998), a patient photograph and cranial CT scan were included that showed nearly identical features. In contrast, the patients described by Shanske et al. (1997) had 'significant frontal recession' and normal skeletal surveys.

Warman et al. (1998) pointed out that although the presence of ectodermal abnormalities in the patients of Marshall (1958) had been emphasized, e.g., sparse hair, eyebrows, and eyelashes, the patients, in fact, did not have these; instead, Marshall (1958) thought that his patients had an altered ability to sweat. When comparing his patients with a 32-year-old female control, Marshall (1958) observed that sweat production was 'diminished, perhaps 25% below normal.'

Molecular Genetics

In affected members in a large kindred with Marshall syndrome in which linkage analysis had mapped the phenotype to the 1p21 region, Griffith et al. (1998) demonstrated a splice-donor site mutation in the COL11A1 gene (120280.0002). The results demonstrated allelism of Marshall syndrome with a subset of Stickler syndrome families associated with COL11A1 mutations.

Both Stickler syndrome and Marshall syndrome are dominantly inherited chondrodysplasias characterized by midfacial hypoplasia, high myopia, and sensorineural hearing deficit. Since the characteristics of these syndromes overlap, it has been argued whether they are distinct entities or different manifestations of a single syndrome. Several mutations causing Stickler syndrome had been found in the COL2A1 gene (see, e.g., 120140.0005) and 1 mutation causing Stickler syndrome (120280.0001) and 1 causing Marshall syndrome (120280.0002) had been detected in the COL11A1 gene. By screening patients with Stickler syndrome, Stickler-like syndrome, or Marshall syndrome, Annunen et al. (1999) identified 23 novel mutations of the COL11A1 gene. Genotypic-phenotypic comparisons revealed an association between the Marshall syndrome phenotype and the splicing mutations of the 54-bp exons in the C-terminal region of the COL11A1 gene. Null-allele mutations in the COL2A1 gene led to the typical phenotype of Stickler syndrome. Some patients, however, presented with phenotypes of both Marshall and Stickler syndromes (120280.0003).

Majava et al. (2007) analyzed 44 patients with a phenotype suggestive of Stickler syndrome or Marshall syndrome who were negative for mutations in the COL2A1 gene, and they identified mutations in COL11A1 in 10 patients (see, e.g., 120280.0002 and 120280.0006). Four of the 10 mutation-positive patients were diagnosed with Marshall syndrome, but the remaining 6 showed an overlapping Marshall/Stickler phenotype. Majava et al. (2007) concluded that heterozygous COL11A1 mutations can result in either Marshall syndrome or Stickler syndrome, and also in phenotypes that are difficult to classify with respect to the 2 disorders. A type I vitreous anomaly was diagnosed in a patient with a mutation in COL11A1 (120280.0006), suggesting that the vitreous phenotype does not always allow prediction of the defective gene in Stickler and Marshall syndromes.

Ala-Kokko and Shanske (2009) reported a 3-year-old boy with Marshall syndrome in whom they identified heterozygosity for a splice site mutation in the COL11A1 gene (120280.0012). Mosaicism for the same mutation was demonstrated in his mildly affected mother and believed to be the cause of her less severe manifestations. Ala-Kokko and Shanske (2009) stated that this was the first report of mosaicism in Marshall syndrome.

Nomenclature

Note that the designation 'Marshall syndrome' has sometimes been used for the Marshall-Smith syndrome; see 602535.