Nicolaides-Baraitser Syndrome

A number sign (#) is used with this entry because Nicolaides-Baraitser syndrome (NCBRS) is caused by heterozygous mutation in the SMARCA2 gene (600014) on chromosome 9p24.

Description

Nicolaides-Baraitser syndrome (NCBRS) is characterized by severe mental retardation, early-onset seizures, short stature, dysmorphic facial features, and sparse hair (summary by Sousa et al., 2009).

Clinical Features

Nicolaides and Baraitser (1993) described a 16-year-old female with mental retardation, sparse hair over the scalp with normal eyebrows and eyelashes, prominent lower lip, brachydactyly, and swelling of the interphalangeal joints. Sousa et al. (2009) reported follow-up of the patient reported by Nicolaides and Baraitser (1993) at age 32 years. She developed recurrent refractory seizures at age 3 years. She lost all language in early adulthood, but was social and enjoyed people. She could only walk short distances with a wide-based gait with hips and knees flexed and bent forward. She used a wheelchair most of the time. Physical examination showed short stature, obesity, complete alopecia, skin wrinkling in the face, neck, and distal limbs, eczema, and an overall aged appearance. Dysmorphic features included brachycephaly, deep-set eyes, narrow nasal bridge, broad nasal base and tip, thick flared alae nasi, low columella, broad and long philtrum, ears with thick overfolded helices, wide mouth, large protruding tongue, thick and everted lower vermilion border, and frequent drooling. She had prominent proximal interphalangeal joints and thick terminal phalanges.

Krajewska-Walasek et al. (1996) reported similar manifestations in a 19-year-old male who had the additional feature of cryptorchidism. Microscopic structure of the hair was normal in both patients. Krajewska-Walasek et al. (1996) proposed that this association might be a distinct syndrome.

Morin et al. (2003) reported 2 unrelated patients with short stature, hypotrichosis, brachydactyly with cone-shaped epiphyses, epilepsy, and severe mental delay. The authors suggested that these 2 additional cases confirmed the existence of this rare disorder and suggested that it be designated Nicolaides-Baraitser syndrome.

Sousa et al. (2009) reported 18 patients, including a pair of monozygotic twins, with Nicolaides-Baraitser syndrome. The main clinical features included severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints, and broad distal phalanges. Many had low birth weight and poor growth, and some had microcephaly. The face was typically triangular, with downslanting and narrow palpebral fissures, periorbital sagging of the skin, narrow nasal bridge, and broad nasal tip with upturned nares. The mouth was wide, with a thin upper vermilion border and thick everted lower vermilion border. Some of the features were noted to progress with time. The main differential diagnosis includes Coffin-Siris syndrome (CSS: 135900). Sousa et al. (2009) concluded that NCBRS is a distinct and recognizable entity that may be underdiagnosed.

Of the 36 individuals studied by Van Houdt et al. (2012) with Nicolaides-Baraitser syndrome, 34 were considered to have a certain clinical diagnosis and 2 had an uncertain diagnosis. One-third had prenatal growth retardation and more than half had postnatal growth retardation. All had some degree of intellectual disability. Three of 36 had mild intellectual disability, 9 of 36 had moderate, and in 24 of 36 intellectual disability was severe. Twenty-two of 35 assessed had seizures, 19 of 35 had microcephaly, 35 of 36 had sparse hair, and half had increased skin wrinkling. The vast majority had thick anteverted alae nasi; 31 of 36 had broad philtrum; 29 of 36 had long philtrum; 34 of 36 a large mouth; 27 of 36 had thin upper vermilion border; 32 of 36 had thick lower vermilion border; 28 of 35 had prominent interphalangeal joints; 21 of 35 had prominent distal phalanges; and 16 of 32 had short metacarpals and/or metatarsals.

Wolff et al. (2011) reported 3 patients with typical Nicolaides-Baraitser syndrome. One patient, who carried a heterozygous missense mutation, had remarkably good developmental progress at age 9 years. He had a borderline IQ of 74 with no autistic features. The other 2 patients reported by Wolff et al. (2011) had severe intellectual disability and autistic features, as well as the typical dysmorphic features noted in Nicolaides-Baraitser syndrome. Wolff et al. (2011) remarked that their findings extended the phenotypic spectrum to include borderline intelligence.

Mari et al. (2015) reported 8 unrelated patients with NCBRS who carried heterozygous missense mutations in the SMARCA2 gene. The patients were ascertained from a cohort of 11 patients with a phenotype consistent with NCBRS or Coffin-Siris syndrome who were screened for mutations in the 6 genes of the BAF complex. All had delayed development with very poor speech, coarse facies, low anterior hairline, sparse scalp hair, large mouth with thick lower lip vermilion, and prominent interphalangeal joints. More variable features included thick eyebrows, synophrys, long eyelashes, broad nose with upturned nasal tip and anterverted nares, hypotonia, seizures, feeding problems, and eczema. Functional studies of the variants were not performed.

Molecular Genetics

Van Houdt et al. (2012) sequenced the exomes of 10 individuals with Nicolaides-Baraitser syndrome and identified heterozygous variants in SMARCA2 in 8 of them. Extended molecular screening identified nonsynonymous SMARCA2 mutations in 36 of 44 individuals with NCBRS; these mutations were confirmed to be de novo when parental samples were available. SMARCA2 encodes the core catalytic unit of the SWI/SNF ATP-dependent chromatin remodeling complex that is involved in the regulation of gene transcription. The mutations cluster within the sequences that encode ultraconserved motifs in the catalytic ATPase region of the protein. These alterations likely do not impair SWI/SNF complex assembly but may be associated with disrupted ATPase activity.

Wolff et al. (2011) reported 3 patients with Nicolaides-Baraitser syndrome and heterozygous de novo mutations in SMARCA2. Two patients had missense mutations in the C-terminal helicase domain and 1 had an in-frame deletion. One patient with a missense mutation had remarkably good developmental progress (600014.0014).

Nomenclature

The acronym used by some for Nicolaides-Baraitser syndrome, NBS, is also used for Nijmegen breakage syndrome (251260), a distinct disorder.