Fryns-Aftimos syndrome (also known as Baraitser-Winter syndrome 1, or BWS1) is a rare chromosomal condition and is associated with

pachygyria Pachygyria ( gyri) is a congenital malformation of the cerebral hemisphere. It results in unusually thick convolutions of the cerebral cortex. Typically, children have developmental delay and seizures, the onset and severity depending on the seve ...

, severe

mental retardation Intellectual disability (ID), also known as general learning disability (in the United Kingdom), and formerly mental retardation (in the United States), Rosa's Law, Pub. L. 111-256124 Stat. 2643(2010).Archive is a generalized neurodevelopmental ...

epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...

and characteristic facial features. This syndrome is a malformation syndrome, characterized by numerous facial dysmorphias not limited to

hypertelorism Hypertelorism is an abnormally increased distance between two organs or bodily parts, usually referring to an increased distance between the orbits (eyes), or orbital hypertelorism. In this condition, the distance between the inner eye corners, a ...

, iris or retinal

coloboma A coloboma (from the Greek , meaning "defect") is a hole in one of the structures of the eye, such as the iris, retina, choroid, or optic disc. The hole is present from birth and can be caused when a gap called the choroid fissure, which is ...

cleft lip A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nasal cavi ...

, and

congenital heart defect A congenital heart defect (CHD), also known as a congenital heart anomaly, congenital cardiovascular malformation, and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital h ...

s. This syndrome has been seen in 30 unrelated people. Characterized by a ''de novo'' mutation located on chromosome 7p22, there is typically no family history prior to onset. The severity of the disorder can be determined by the size of the deletion on 7p22, enveloping the ACTB gene and surrounding genes, which is consistent with a contiguous gene deletion syndrome. Confirming a diagnosis of Fryns-Aftimos syndrome typically consists of serial single-gene testing or multigene panel of genes of interest or

exome sequencing Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome). It consists of two steps: the first step is to select only the subs ...

Signs and symptoms

Fryns-Aftimos syndrome is a genetic conditions that presents with a multitude of varying signs, symptoms and characteristics facies. Commonly characterized by

congenital nonmyopathic ptosisiris or retinal coloboma

deafness Deafness has varying definitions in cultural and medical contexts. In medical contexts, the meaning of deafness is hearing loss that precludes a person from understanding spoken language, an audiological condition. In this context it is writte ...

, and

. Individuals affected by Fryns-Aftimos syndrome may also present with a broad nose that has a large tip and prominent root, a ridged

metopic suture The frontal suture is a fibrous joint that divides the two halves of the frontal bone of the human skull, skull in infants and children. Typically, it completely fuses between three and nine months of age, with the two halves of the frontal bone ...

, arched eyebrows, a shoulder girdle muscle bulk and progressive joint stiffness, a cleft lip or palate, hallux duplex (a toe deformation),

microcephaly Microcephaly (from Neo-Latin ''microcephalia'', from Ancient Greek μικρός ''mikrós'' "small" and κεφαλή ''kephalé'' "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it m ...

, heart and renal tract abnormalities; all which contribute to the intellectual and developmental disabilities exhibited by affected individuals. Consequentially, it has been observed that those with this syndrome also have a short stature and the presence of an extra (duplicated) thumb. The presentation and severity of the previously mentioned symptoms vary depending on the severity of the syndrome. Some individuals may be affected by all the discussed symptoms, and some may have only one or two. For example, the pachygyria associated with Fryns-Aftimos syndrome is rarely

lissencephaly Lissencephaly (, meaning 'smooth brain') is a set of rare brain disorders whereby the whole or parts of the surface of the brain are smooth. It is caused by defective neuronal migration during the 12th to 24th weeks of gestation, resulting in a ...

, o
neuronal heterotopia
Additionally, the associated microcephaly is not a required, it can develop over time as the affected individual continues to live. Those who have diagnosed condition have differing degrees of the following:

Etiology

"BWS is a genetically heterogeneous disorder, caused by a heterozygous mutation in one of the 2 genes coding for ubiquitously expressed actins:

ACTB Actin beta (HUGO Gene Nomenclature Committee abbreviation ''ACTB''/ACTB) is one of six different actin isoforms which have been identified in humans. This is one of the two nonmuscle cytoskeletal actins. Actins are highly conserved proteins that ...

, located to 7p22-p12 (BRWS1) and

ACTG1 Actin, cytoplasmic 2, or gamma-actin is a protein that in humans is encoded by the ''ACTG1'' gene. Gamma-actin is widely expressed in cellular cytoskeletons of many tissues; in adult striated muscle cells, gamma-actin is localized to Z-discs and ...

on 17q25.3 (BRWS2). All mutations are

missense In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Missense mutations change amino acids, which in turn al ...

and probably act by a gain of function mechanism, as deletions of the same genes do not result in BWS phenotype." Functional copies of ACTB and ACTG1 genes provide instructions for protein production of beta (β)-actin and gamma (γ)-actin, respectively. As an intrinsic disorder, current research indicates that mutations in an individual's DNA are responsible for expression. In recent years, studies have been conducted to determine the extent of causative mutations affecting the ACTB gene. In order to determine the functionality and effect of certain mutations,

whole-exome sequencing Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome). It consists of two steps: the first step is to select only the subset ...

(WES) has been employed upon "aborted fetuses and children with syndromic brain malformations in which chromosomal microarray analysis was previously unremarkable." Fryns-Aftimos syndrome has an autosomal dominant inheritance pattern caused by a

heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...

mutation in the

gene on chromosome 7p22. This mutation occurs ''

de novo De novo (Latin, , used in English to mean 'from the beginning', 'anew') may refer to: Science and computers * ''De novo'' mutation, a new germline mutation not inherited from either parent * ''De novo'' protein design, the creation of a protei ...

,'' typically meaning there is no family history prior to onset; the disorder presents for the first time in a family in the affected individual. However, once present Fryns-Aftimos syndrome is characterized by an autosomal dominant inheritance pattern, as previously mentioned, which means that individuals with a heterozygous or homozygous dominant genotype will display the phenotypic traits associated with the syndrome. The severity of symptoms are linked to the size of the deletion on chromosome 7p22 because certain individuals may have a larger deletion on 7p22, enveloping the ACTB gene and surrounding genes, which is consistent with a contiguous gene deletion syndrome.

Diagnosis

BWS can be detected prenatally from the occurrence of abnormal gyration patterns in the fetus. Care should be employed when performing antenatal diagnoses as miscarriage and other complications are possible. The diagnosis of unremarkable prenatal scans can be supplemented through the use of WES or trio sequencing. BWS diagnoses are commonly confirmed via DNA sequencing of ACTB and ACTG1 genes. Serial single-gene testing performs a sequence analysis of ACTB followed by ACTG1. It is important to note that deletion/duplication analysis is not a possible method of diagnosis as all associated mutations are missense in nature. Multigene panels are employed to differentiate BWS from different mutations with similar phenotypic characteristics such as

Noonan syndrome Noonan syndrome (NS) is a genetic disorder that may present with mildly unusual facial features, short height, congenital heart disease, bleeding problems, and skeletal malformations. Facial features include widely spaced eyes, light-colored ...

. Associated genes analyzed in multigene panels for BWS include KIF5C, KIF2A, DYNC1H1, WDR62, and TUBG1 genes.

Management

Educative measures can partially manage developmental delays, with success variable on the degree of severity. Management of epilepsy is difficult, and some pachygyria patients are drug resistant, including to combination therapies. Orthopedic monitoring is mandatory, since progressive join limitations could lead to loss of autonomous ambulation. Treatment of Fryns-Aftimos syndrome is similar to other developmental disorders in which speech and physical therapy are offered as a mechanism through which to manage associated characteristics of developmental delay. The frequency and duration of treatment is largely dependent upon the severity of the disability itself. Since Fryns-Aftimos syndrome is commonly characterized by

, individuals may experience chronic seizures that can be treated with anti-epileptic drugs (AEDs). Medical surveillance is highly recommended for those with more severe forms of BWS. Routine follow ups are recommended for neurodevelopmental assessment with particular emphasis upon coloboma (ophthalmologic evaluation), hearing loss (audiologic evaluation), cardiac defects, and renal tract anomalies.

References

External links