Nicolaides-Baraitser syndrome (NCBRS)

What is Nicolaides-Baraitser syndrome (NCBRS)?

Nicolaides-Baraitser syndrome is a very rare genetic condition with just 75 known recorded cases. to date.

Common symptoms of the syndrome include, severe mental retardation, short stature, sparse hair, early-onset seizures, and characteristic facial features.

This syndrome is also known as:
Nbs NCBRS Sparse Hair And Mental Retardation

What gene changes cause Nicolaides-Baraitser syndrome (NCBRS)?

The syndrome is caused by a mutation in the SMARCA2 gene. Mutations are de novo and the condition is not inherited.

In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

What are the main symptoms of Nicolaides-Baraitser syndrome (NCBRS)?

Facial and physical characteristics include, a triangular face, sparse scalp hair, microcephaly, a short stature, prominent finger joints, exceptionally short fingers and toes, deep-set eyes, a thin nasal bridge, wide nostrils and a thick lower lip.

Individuals with the syndrome usually have a lack of subcutaneous fat under their facial skin which leads to early wrinkling of the skin, visible veins and pale skin.

Other health conditions may include severe seizures and epilepsy, moderate-several intellectual disability and limited to zero speech development. ⅓ of all individuals with the syndrome will have no speech.

Feeding issues and problems are also common to the syndrome, as are umbilical or inaugural hernias. Some individuals may experience genital and dental abnormalities.

Possible clinical traits/features:
Wide mouth, Thin vermilion border, Widely spaced teeth, Seizure, Poor speech, Long philtrum, Low anterior hairline, Narrow nasal bridge, Unilateral narrow palpebral fissure, Neurological speech impairment, Anteverted nares, Intrauterine growth retardation, Intellectual disability, severe, Scoliosis, Microcephaly, Broad philtrum, Thick lower lip vermilion, Triangular face, Sandal gap, Wide nasal base, Sparse scalp hair, Prominent interphalangeal joints, Abnormal hair quantity, Short metacarpal, Short metatarsal, Accelerated skeletal maturation, Absent speech, Aggressive behavior, Blepharophimosis, Abnormal palate morphology, Abnormal nipple morphology, Abnormality of the metacarpal bones, Abnormal joint morphology, Abnormal eyelash morphology, Abnormality of epiphysis morphology, Abnormal distal phalanx morphology of finger, Hernia, Highly arched eyebrow, Cognitive impairment, Short phalanx of finger, Short stature, Clubbing of toes, Malformation of the heart and great vessels, Failure to thrive

How does someone get tested for Nicolaides-Baraitser syndrome (NCBRS)?

The initial testing for Nicolaides-Baraitser syndrome (NCBRS) can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Nicolaides-Baraitser syndrome (NCBRS)

DISEASE OVERVIEW:
Nicolaides-Baraitser syndrome (NCBRS) is a rare, autosomal dominant disorder characterized by intellectual disability (severe in about 50%), sparse scalp hair, characteristic coarse facies, microcephaly, seizures, short stature, and prominent interphalangeal joints. Regressions can occur with seizure onset, typically in speech, and nearly one third of patients never develop speech. NCBRS is caused by heterozygous pathogenic variants in SMARCA2 and all reported cases have been de novo. SMARCA2 encodes a subunit in the BAF chromatin remodeling complex, which is involved in gene transcription, cell differentiation, and DNA repair.

CLINICAL DESCRIPTION (GENERAL):
Nicolaides-Baraitser syndrome (NCBRS) is characterized by sparse scalp hair, prominence of the inter-phalangeal joints and distal phalanges due to decreased subcutaneous fat, characteristic coarse facial features (anteverted nares, long philtrum, wide mouth with thin upper lip vermilion and thick lower lip vermilion), microcephaly, seizures, and intellectual disability. Seizures are of various types and are often difficult to manage. The mean age of onset of seizures is 24 months with a range of birth to 14 years. Developmental delay/intellectual disability is severe in nearly half, moderate in one third, and mild in the remainder. Nearly a third never develop speech or language skills.

CLINICAL DESCRIPTION (BODY SYSTEMS):
Bones and joints: prominence of inter-phalangeal joints and distal phalanges, brachydactyly. Skeletal X-rays may reveal cone-shaped epiphyses, metaphyseal flaring of the phalanges, shortening of the phalanges, metacarpals, and metatarsals, platyspondyly, pubic bone hypoplasia and small femoral heads with short femoral neck.
Nervous system: developmental delay/intellectual disability, seizures, microcephaly
Skin and hair: sparse scalp hair, poor subcutaneous fat distribution, reduced skin pigmentation

SYNDROME CHARACTERISTICS:
PENETRANCE: Data are insufficient to determine. All reported cases are de novo, suggesting penetrance is likely complete.
PREVALENCE: Rare, <100 cases reported in the literature
LIFE EXPECTANCY: Unknown
AGE OF ONSET: Congenital. Many features show age-related penetrance.
PRENATAL PRESENTATION: Low birth weight, microcephaly

MOLECULAR GENETICS:
RECURRENT MUTATION(S): N/A
TYPE OF MUTATION(S): Most are missense mutations, but partial gene deletions have been reported.
GENOTYPE/PHENOTYPE CORRELATION: No clear genotype-phenotype correlations. All individuals with pathogenic variants in the C-terminal helicase region of the ATPase domain have severe intellectual disability and epilepsy. Mutations at residues Pro883, Leu946, and Ala1201 may be associated with a milder phenotype.

KEY CLINICAL FEATURES/PHENOTYPES:
Abnormality of the nervous system; developmental delay/intellectual disability in 100%, microcephaly in 65%, seizures in 64%, behavioral issues in at least 21 patients, autism in two patients, absent speech in nearly 1/3
Abnormality of the head and neck; coarse facies (*triangular facies, *anteverted nares, *long philtrum, *wide mouth, *thin upper lip vermillion and *thick lower lip vermillion) in 77%, hearing loss in 4/59 patients, delayed tooth eruption
Abnormality of the eye; myopia in 10 patients, astigmatism in 4 patients
Abnormality of the cardiovascular system; various congenital heart defects in 6 reported cases
Abnormality of the skeletal system; prominent interphalangeal joints in 85%, cone-shaped epiphyses, metaphyseal flaring of the phalanges, shortening of the phalanges, metacarpals, and/or metatarsals (especially the 4th and 5th rays), variable bone age, platyspondyly, flat intervertebral discs, small pelvis, pubic bone hypoplasia, small femoral heads, short femoral necks
Growth abnormality; low birth weight in 50%, short stature in 50%
Abnormality of the integument; sparse scalp hair in 97%, poor subcutaneous fat distribution, reduced skin pigmentation
Abnormality of the of the genitourinary system; cryptorchidism in most males

KEY PUBLICATIONS:
Nicolaides and Baraitser described the first case of NCBRS in 1993 (Nicolaides, 1993). Sousa et al described 18 additional patients in addition to the 6 previously described cases, allowing the establishment of NCBRS as a discrete syndrome (Sousa, 2009). Van Houdt et al. identified SMARCA2 as the genetic cause of NCBRS (Van Houdt, 2012). Sousa et al described 61 molecularly confirmed cases of NCBRS, including the 47 previously reported patients and 14 additional unpublished patients, characterizing the cardinal features and genotype-phenotype correlations (Sousa, 2014). Mari et al described the overlap of phenotype with NCBRS and Coffin-Siris syndrome (Mari, 2015) .

SURVEILLANCE:
At least yearly neurology evaluation to assess for and/or manage seizures.
Yearly developmental pediatrician evaluation.
Regular follow-up of ophthalmologic and/or audiologic abnormalities.

MANAGEMENT AND TREATMENT:
Antiepileptic drugs for seizures under the care of a neurologist or epileptologist.
Occupational, physical, and/or speech therapy.
Routine management of refractive errors and hearing loss.

CLINICAL TRIALS:
N/A

PATIENT ORGANIZATIONS:
NCBRS Parent Support, www.ncbrs.com


(1)Department of Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center
[email protected]
https://www.unmc.edu/mmi/departments/geneticmed/index.html


DATE OF UPDATE:
July 9, 2018

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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