Coffin-Siris Syndrome 1

A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-1 (CSS1) is caused by heterozygous mutation in the ARID1B gene (614556) on chromosome 6q25.

Description

Coffin-Siris syndrome is a multiple malformation syndrome characterized by mental retardation associated with coarse facial features, hypertrichosis, sparse scalp hair, and hypoplastic or absent fifth fingernails or toenails. Other more variable features may include poor overall growth, craniofacial abnormalities, spinal anomalies, and congenital heart defects (review by Vergano and Deardorff, 2014). Mutations in the ARID1B gene are the most common cause of Coffin-Siris syndrome (Wieczorek et al., 2013).

Genetic Heterogeneity of Coffin-Siris Syndrome

Forms of Coffin-Siris syndrome have been shown to be caused by mutations in genes encoding subunits of the SWI/SNF complex, also known as the BAF complex, which functions as a chromatin remodeling factor. These include CSS2 (614607), caused by mutation in the ARID1A gene (603024); CSS3 (614608), caused by mutation in the SMARCB1 gene (601607); CSS4 (614609), caused by mutation in the SMARCA4 gene (603254); CSS5 (616938), caused by mutation in the SMARCE1 gene (603111); CSS6 (617808), caused by mutation in the ARID2 gene (609539); CSS7 (618027), caused by mutation in the DPF2 gene (601671); CSS8 (618362), caused by mutation in the SMARCC2 gene (601734); CSS9 (615866), caused by mutation in the SOX11 gene (600898); and CSS10 (618506), caused by mutation in the SOX4 gene (184430).

A similar phenotype, Nicolaides-Baraitser syndrome (NCBRS; 601358), is also caused by mutation in a subunit of this complex, i.e., SMARCA2 (600014).

Clinical Features

Coffin and Siris (1970) described 3 unrelated girls with mental retardation and absent nail and terminal phalanx of the fifth finger. The nails and distal phalanges of the lateral toes were either absent or hypoplastic. No similar cases were found in any of the 3 families.

Poyhonen et al. (2004) reported 3 unrelated Finnish females with hypertrichosis, mild to moderate mental retardation, and dysmorphic facial features, including low anterior hairline, thick arched eyebrows, nose with broad tip and columella below alae nasi, short philtrum, thick drooping lower lip, and simple posteriorly rotated ears. The patients also had rough skin with hyperkeratotic plaques. Feet and finger tips were broad. Brain MRI showed thick and short corpus callosum. Zweier et al. (2017) reported follow-up of the 3 Finnish women reported by Poyhonen et al. (2004), who were 25 (P1), 26 (P2), and 19 (P3) years of age. Clinical reassessment of the patients revealed the previously described phenotype, although hypertrichosis was less apparent and even considered within the normal range. Additional features included mild short stature, myopia, strabismus, coarse facies, and mild nail hypoplasia. The patients had significant behavioral abnormalities, including severe obsessive-compulsive disorder, withdrawal, stubborn and obstinate behavior, and autistic features. Language was limited, and they were noted to have a hoarse or high-pitched voice. However, all were able to read, write, and count. Menarche occurred normally. As an infant, patient 2 had a ventricular septal defect, patent ductus arteriosus, mild coarctation of the aorta, and hip dislocation.

Hoyer et al. (2012) reported 8 unrelated patients with mental retardation. All patients presented with moderate to severe psychomotor retardation, and most showed evidence of muscular hypotonia. In many patients, expressive speech was reported to be more severely affected than receptive function. Although there was no distinct recognizable facial gestalt, common findings included short stature, abnormal head shape and low-set, posteriorly rotated, and abnormally shaped ears, downslanting palpebral fissures, a bulbous nasal tip, a thin upper lip, minor teeth anomalies, and brachydactyly or single palmar creases. Only 1 patient had autistic features.

Tsurusaki et al. (2012) reported 5 patients with Coffin-Siris syndrome. All 5 patients had developmental delay and absent or hypoplastic fifth fingernails/toenails with absent/hypoplastic fifth phalanx of the hand; all had hirsutism and a coarse facial appearance with flat nasal bridge, broad nose, and thick lips. Frequent infections were reported in all of the patients.

Santen et al. (2012) reported 3 patients with Coffin-Siris syndrome who had moderate to severe intellectual disability and severe speech delay. All had coarse facial features with thick eyebrows and low frontal hairline; hypertrichosis was also present in all. Two had fifth finger brachydactyly; one of these and the other patient without brachydactyly had a hypoplastic nail on the fifth finger. Two had agenesis of the corpus callosum and one had partial agenesis. Three additional subjects with deletions involving ARID1B had some facial similarities with the patients carrying truncation mutations but lacked hypoplastic or absent fingernails or toenails. Santen et al. (2012) noted that few affected individuals in published reports fulfill the complete spectrum of the CSS phenotype, and it is a subject of debate whether all individuals with CSS represent the same entity.

Other Features

Mattei et al. (1981) reported 2 affected sisters of North African origin. One sister had massive unilateral hydronephrosis. Consanguinity was suspected, but not proven, and autosomal recessive inheritance was suggested. As noted by Gorlin (1981), the sibs reported by Mattei et al. (1981) had Coffin-Siris syndrome, not Coffin-Lowry syndrome (303600) as originally reported.

Haspeslagh et al. (1984) analyzed 23 published cases of Coffin-Siris syndrome. The female:male ratio was about 4:1.

Qazi et al. (1990) described a white female infant with the typical features of Coffin-Siris syndrome including thick eyebrows, flat nasal bridge, anteverted and wide nasal tip, generalized hypertrichosis, scalp hypotrichosis, absence of the fifth fingernails and toenails, absence of the distal phalanges of the fifth fingers and of the second to fifth toes, small patellas, inguinal hernia, and sucking and feeding difficulties. There was decreased fetal activity and intrauterine growth retardation.

Rabe et al. (1991) described 2 sisters, 3 and 6 years of age, with a disorder resembling Coffin-Siris syndrome. Both sibs had developmental retardation, facial and skeletal anomalies, and hyperphosphatasia. A major diagnostic clue was hypoplasia/aplasia of the terminal phalanx of the fifth finger, recognized radiologically.

Swillen et al. (1995) presented data on cognitive development, language, behavior, and social skills of 9 girls and 3 boys, aged 2.5 to 19 years, with Coffin-Siris syndrome. Mental retardation was mild in 3 patients and moderate in 9 others. Speech development was severely retarded with little interest in language. In the 7 patients aged 7 to 19 years, language comprehension was appropriate to the mental level. Gross motor functioning and autonomy, with the lowest score on 'task orientation,' were equal to the mental development. Most frequently, aggressive disturbed behavior was observed, especially in the youngest children, while mixed disturbed behavior was observed in the oldest patients. Five of 12 patients presented symptoms of pervasive developmental disorder, with 2 of the 11 scoring in the pathologic range. Obsessive interests, strong dependence on patterns and rituals, and unusual fears were characteristic behavioral problems also when the children got older.

Bonioli et al. (1995) described a family in which 3 sisters with first-cousin parents had a phenotype resembling Coffin-Siris syndrome. Hypoplasia of the distal phalanges and mental retardation were features. Two of the sisters died at 10 days and 1 day of age of cardiac abnormalities. At the age of 16 months, the surviving sister showed hypertrichosis, synophrys, umbilical hernia, rectal prolapse, bilateral clinodactyly of the fifth finger with hypoplastic nails, and lesser hypoplasia of the other nails and distal phalanges.

Fleck et al. (2001) reviewed Coffin-Siris syndrome and reported 18 new cases. The most frequent findings included some degree of mental retardation or developmental delay, coarse facial appearance, feeding difficulties, frequent infections, and hypoplastic to absent fifth fingernails and fifth distal phalanges.

DeBassio et al. (1985) described seemingly typical abnormalities of the hindbrain in patients with Coffin-Siris syndrome. The authors noted that the Dandy-Walker malformation (220200) was present in the original case of Coffin and Siris (1970) and in the case of Tunnessen et al. (1978). Imai et al. (2001) described a male infant with typical Coffin-Siris syndrome and the Dandy-Walker malformation complex, characterized by hypoplasia of the cerebellar vermis and cystic dilatation of the fourth ventricle without enlargement of the posterior fossa, as well as partial agenesis of the corpus callosum. The authors stated that this infant confirms that the full continuum of the Dandy-Walker complex can occur in Coffin-Siris syndrome.

Burlina et al. (1990) found partial biotinidase deficiency (see 253260) in association with the Coffin-Siris syndrome; Bonneau et al. (1991) were unable to confirm this finding.

DeJong and Nelson (1992) described choanal atresia (608911) in 2 unrelated patients with the Coffin-Siris syndrome.

Imaizumi et al. (1995) described a patient with Coffin-Siris syndrome who presented at 4 months of age with recurrent hypoglycemia attacks. Detailed examination at the age of 7 months revealed no cause of the hypoglycemia.

Brunetti-Pierri et al. (2003) reported an Italian girl with Coffin-Siris syndrome who had premature thelarche. At age 12 months, she had bilateral breast enlargement, accelerated linear growth, and advanced bone age. No exogenous exposure to estrogen compounds was found, endogenous hormone levels were normal, and there was no evidence of precocious puberty (see 176400). The thelarche completely regressed by age 2.5 years. Flynn and Milunsky (2006) reported a mother and 2 daughters of Jamaican origin who had some of the features of Coffin-Siris syndrome, but could be excluded from the strict clinical diagnosis because of hypertelorism and relatively mild coarse facial features. One of the daughters demonstrated premature thelarche at age 11 months which had resolved by age 6 years 7 months. The authors suggested autosomal dominant inheritance in this family.

Kellermayer et al. (2007) reported an 8-year-old Latina girl with features consistent with Coffin-Siris syndrome, including patent ductus arteriosus, developmental delay, frequent respiratory infections, microcephaly, facial dysmorphism, hearing loss, sacral dimple, and sternal and digital anomalies. She developed recurrent episodes of emesis with lower abdominal pain. Gastrointestinal studies showed a lengthy, redundant duodenum without obstruction and a heterotopic pancreatic rest at the pyloric orifice, as well as 2 papillary structures in the duodenum. The findings broadened the variable upper gastrointestinal manifestations of the disorder, but the etiology of the patient's recurrent emesis remained unclear.

Baban et al. (2008) described an 8.5-year-old girl with classic features of Coffin-Siris syndrome as well as a structural brain malformation and endocrinologic deficiency not previously reported in CSS patients. Cerebral MRI at 3.5 years of age showed global hypoplasia of the pituitary gland with an ectopic neurohypophysis along the course of the pituitary stalk, dysmorphic corpus callosum, and mega cisterna magna; she also had growth hormone deficiency, treated with recombinant GH with significant clinical improvement.

Diagnosis

Fleck et al. (2001) proposed developmental delay, coarse facial appearance, hirsutism, and hypoplastic or absent fifth distal phalanges as minimal diagnostic criteria for the diagnosis of Coffin-Siris syndrome.

Differential Diagnosis

Senior (1971) described 6 unrelated children who had broad nose with prominent nares and mild mental retardation in addition to short stature and small fifth toenails. These children may have had a distinct disorder, which Verloes et al. (1993) called brachymorphism-onychodysplasia-dysphalangism (BOD) syndrome (113477).

Brautbar et al. (2009) described a 7-year-old girl with hypoplastic nails, especially on the 5th digit of each extremity, which were more noticeable on the feet, coarse face, broad nose, wide mouth, thick eyebrows, long eyelashes, accommodative esotropia, inguinal and umbilical hernia, large premium atrial septal defect and cleft mitral valve, hirsutism, and mild developmental delay. Brautbar et al. (2009) suggested that even though the patient met the minimal clinical diagnostic criteria of CSS, some features, such as mild developmental delay and the more severe involvement of the feet when compared to the hands, were more consistent with BOD syndrome. Brautbar et al. (2009) suggested that CSS and BOD syndrome are probably allelic disorders.

Hanson et al. (1976) noted that hypoplastic nails and terminal phalanges can also be found in the fetal anticonvulsant syndrome. The second patient reported by Weiswasser et al. (1973) was subsequently published as an example of fetal hydantoin syndrome by Hanson and Smith (1975).

Fryns (1986) suggested that some reported cases of Cornelia de Lange syndrome (122470) may in fact be cases of Coffin-Siris syndrome. Musio et al. (2006) reported 5 cases of X-linked Cornelia de Lange syndrome (300590) and noted overlapping features with Coffin-Siris syndrome.

Inheritance

Carey and Hall (1978) reported affected brother and sister and Franceschini et al. (1986) described affected sibs, suggesting autosomal recessive inheritance. Richieri-Costa et al. (1986) reported a child with Coffin-Siris syndrome born of consanguineous parents, consistent with autosomal recessive inheritance.

Haspeslagh et al. (1984) reported 2 affected sisters and partial expression in their father. The authors noted that Tunnessen et al. (1978) had also reported partial expression in 1 parent, and suggested autosomal dominant inheritance with variable expression.

Levy and Baraitser (1991) reviewed 31 reported cases and added 2 new cases. They noted that a case reported by Baraitser and Winter (1983) in an atlas of clinical genetics was subsequently shown to have trisomy 9p. Levy and Baraitser (1991) concluded that evidence for recessive inheritance was not fully convincing and suggested that some of the published single cases and even sibships may prove to be chromosomal rather than mendelian in nature. Levy and Baraitser (1991) stated that their practice is to counsel a 10% recurrence risk.

Cytogenetics

McGhee et al. (2000) described an 11-year-old girl with Coffin-Siris syndrome and a de novo, apparently balanced reciprocal translocation, t(7;22)(q32;q11.2). The 7q breakpoint in this patient was very similar to that reported by McPherson et al. (1997) with a balanced t(1;7)(q21.3;q34). Together, these patients provided evidence that the 7q32-q34 region contains the gene responsible for Coffin-Siris syndrome.

Molecular Genetics

Hoyer et al. (2012) performed Sanger sequencing of candidate genes, including ARID1B, in a region on chromosome 6q25 that was deleted in a patient with mental retardation (see 612863). A total of 8 mutations in the ARID1B gene (see, e.g., 614556.0001-614556.0005) were found in 8 (0.9%) of 887 individuals with mental retardation. All mutations were in the heterozygous state, occurred de novo, and resulted in haploinsufficiency of the ARID1B gene. Given the known function of ARID1B, the findings indicated that chromatin-remodeling defects are an important contributor to neurodevelopmental disorders.

In 5 patients with Coffin-Siris syndrome, Tsurusaki et al. (2012) identified 4 nonsense or frameshift mutations in ARID1B (e.g., 614556.0006, 614556.0007), which encodes a subunit of the SWI/SNF complex. Three of these mutations occurred de novo. One of the patients carried a microdeletion involving ARID1B. In a total of 20 affected individuals with a similar constellation of clinical features, Tsurusaki et al. (2012) identified germline mutations in one of 6 SWI/SNF subunit genes.

By exome sequencing, Santen et al. (2012) identified 3 de novo truncating mutations in the ARID1B gene (614556.0008-614556.0010) in individuals with syndromic mental retardation. Array-based copy number variation analysis in 2,000 individuals with intellectual disability revealed an additional 3 subjects with a deletion affecting ARID1B.

Using a combination of whole-exome sequencing, next-generation sequencing of 23 SWI/SNF complex genes, and molecular karyotyping, Wieczorek et al. (2013) identified mutations in 28 (60%) of 46 patients with a clinical phenotype consistent with Coffin-Siris syndrome or Nicolaides-Baraitser syndrome (NCBRS; 601358), which shows similar features. Mutations in the ARID1B gene accounted for 76% of the identified mutations, and all of the mutations were truncating, resulting in haploinsufficiency. Wieczorek et al. (2013) observed that patients with ARID1B mutations had a milder phenotype, with hypoplastic rather than absent finger- and toenails, fewer growth defects, and fewer additional congenital anomalies compared to patients with mutations in other genes. Some of the patients with ARID1B mutations had an initial diagnosis of NCBRS, suggesting that these syndromes may represent a phenotypic spectrum rather than 2 distinct disorders. Functional studies of the variants and studies of patient cells were not performed.

By screening 6 genes of the BAF complex in 63 patients with a clinical diagnosis of CSS, Santen et al. (2013) identified pathogenic variants in 71% of patients. ARID1B mutations were the most common, found in 28 patients, and thus accounted for 68% of the mutation load. All ARID1B mutations occurred de novo and resulted in a truncated protein. Functional studies of the variants and studies of patient cells were not performed.

In 2 (P2 and P3) of 3 unrelated Finnish women with CSS1, originally reported by Poyhonen et al. (2004), Zweier et al. (2017) identified de novo heterozygous frameshift mutations in the ARID1B gene (614556.0011 and 614556.0012). The mutations, which were found by trio-based exome sequencing in the patients and their parents, were confirmed by Sanger sequencing. Functional studies of the variants were not performed, but both were predicted to result in a loss of function and haploinsufficiency. The patients were originally reported as having a different disorder (HHID), but the findings of Zweier et al. (2017) confirmed that the patients had CSS1. Genetic analysis of the other patient (P1) reported by Poyhonen et al. (2004) did not reveal pathogenic mutations or copy number variations affecting the ARID1B gene, but the father was not available for study. Zweier et al. (2017) could not exclude a pathogenic noncoding variant in P1.

Associations Pending Confirmation

See 604958 for discussion of a possible association between variation in the ACTL6A gene and a form of Coffin-Siris syndrome.