Acrocallosal syndrome

Acrocallosal syndrome
Classification and external resources
OMIM	200990
MeSH	D055673

Acrocallosal syndrome (also known as ACLS) is a rare autosomal recessive syndrome characterized by corpus callosum agenesis, polydactyly, multiple dysmorphic features, motor and mental retardation, and other symptoms.^[1] The syndrome was first described by Albert Schinzel in 1979.^[2]

It is associated with GLI3.^[3]

Signs and Symptoms

Acrocallosal syndrome (ACLS, ACS, Schinzel-Type, Hallux-duplication) is a rare, heterogeneous [3] autosomal recessive disorder first discovered by Albert Schinzel (1979) in a 3-year-old boy [1]. To inherit ACLS, one gene copy from each parent must contain a mutation somewhere in the KIF7 gene and be passed on to the child [3]. Characteristics of this syndrome include absence or poor development of the area connecting the left and right parts of the brain, an abnormally large head, increased distance between facial features (eyes), poor motor skills, mental retardation [2], extra fingers and toes, many facial deformities [3], and cleft palate [5]. This is considered a rare disorder and is placed on the NIH Office of Rare Diseases (fewer than 200,000 cases) rare disease list [8]. Lifespan may range from stillbirth to normal expectancy depending on pregnancy complications and severity of the disorder [2,3,5]. In mild cases, the subjects have been shown to live relatively normal lives, but with developmental delays [2].

Pathology

Acrocallosal syndrome (ACLS, ACS, Schinzel-Type) is a rare, heterogeneous, autosomal recessive disorder [3]. The heterogeneity of this condition refers to the multiple genes that may function to contribute to varying degrees of this syndrome [3] and is often linked to consanguinity [2,5]. Characteristics of this syndrome include agenesis of the corpus, macrocephaly, hypertelorism, polydactyly, mental and motor retardation [2], craniofacial dysmorphism, hallux dudplication [3], and sometimes palatal clefting [5]. It has also been reported that there are many similar signs and symptoms between ACLS, Greig cephalopolysyndactyly, and Hydrolethalus Syndrome (HLS), although there is little evidence to support common genetic causation at this point [3].

Mechanism

Recent studies by Putoux et al., (2011), have indicated that the mutations responsible for ACLS are located in the KIF7 protein. KIF7 is a 1343 amino acid protein with a kinesin motor, coiled coil, and Gli-binding domains [3,5]. Its functions are largely associated with ciliary motor function [3] and is a key factor in the Sonic Hedgehog (Shh) transduction pathways [4,5] that are crucial during embryogenesis [7]. Therefore, mutations in Hedgehog signaling components (KIF7) may lead to cilia based pathologies and ultimately defects in the brain and other areas associated with ACLS and related disorders [5]. More specifically, mutations observed by Elson et al., (2002), in the GLI3 gene have yielded similar characteristics to ACLS, but further evidence is needed since the corpus callosum is usually present in these cases. Other studies have also indicated that KIF7 interacts with Gli transcription factors, so mutations in the KIF7 gene may be upstream effectors of GLI3 [6]. Further understanding about the functionality of ACLS and its underlying mechanisms opens new doors to pharmacological manipulation and other forms of molecular therapy.

References

↑ Online 'Mendelian Inheritance in Man' (OMIM) Acrocallosal syndrome; ACLS -200990
↑ Schinzel, Albert (May 1979). "Postaxial polydactyly, hallux duplication, absence of the corpus callosum, macroencephaly and severe mental retardation: a new syndrome?". Helvetica Paediatrica Acta 34 (2): 141–6. PMID 457430.
↑ Elson E, Perveen R, Donnai D, Wall S, Black GC (November 2002). "De novo GLI3 mutation in acrocallosal syndrome: broadening the phenotypic spectrum of GLI3 defects and overlap with murine models". J. Med. Genet. 39 (11): 804–6. doi:10.1136/jmg.39.11.804. PMC 1735022. PMID 12414818.

Koenig R., Bach A., Ulrike W., Grzeschik K-H, Fuchs S. (2002). "Spectrum of the acrocallosal syndrome". American Journal of Medical Genetics 108 (1): 7–11. doi:10.1002/ajmg.10236.

Walsh D., Shalev S., Simpson M., Morgan N., Gelman-Kohan Z., Chemke J., Trembath R., Maher E. (2013). "Acrocallosal syndrome: Identification of a novel KIF7 mutation and evidence for oligogenic inheritance". European Journal of Medical Genetics 56 (1): 39–42. doi:10.1016/j.ejmg.2012.10.004.
Putoux A., Nampoothiri S., Laurent N., Cormier-Daire V., Beales P.; et al. (2012). "Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal sndrome". Journal of Medical Genetics 49 (11): 713–720. doi:10.1136/jmedgenet-2012-101016.
Putoux A., Thomas S., Coene K. L. M., Davis E. E., Alanay Y., Ogur G.; et al. (2011). "KIF7 mutations cause fetal hydrolethalus and acrocallosal syndromes". Nature Genetics 43 (6): 601–606. doi:10.1038/ng.826.
Elson, E., Perveen, R., Donnai, D., Wall, S., and Black, GCM. (2002). De novo GLI3 mutation in acrocallosal syndrome:broadening the phenotypic spectrum of GLI3 defects and overlap with murine models" Journal of Medical Genetics 39, 804-806. Doi: 10.1136/jmg.39.11.804. http://jmg.bmj.com/content/39/11/804.short

Klejnot, M. and Kozielski, F. (2011). Structural insights into human Kif7, a kinesin involved in Hedgehog signaling. Acta Crystallographica Section D, 68(2), 154-159. Doi: 10.1107/S0907444911053042.

NIH Office of Rare Diseases Research. (n.d.). Acrocallosal syndrome, Schinzel type. Bethesda, MD. Retrieved on 2/4/14 from: http://rarediseases.info.nih.gov/gard/5721/acrocallosal-syndrome-schinzel-type/resources/1

External links

Acrocallosal syndrome, Schinzel type at NIH's Office of Rare Diseases

Congenital malformations and deformations of nervous system (Q00–Q07, 740–742)

Brain

Neural tube defect	Anencephaly Acephaly Acrania Acalvaria Iniencephaly Encephalocele Arnold–Chiari malformation

Other	Microcephaly Congenital hydrocephalus Dandy–Walker syndrome other reduction deformities Holoprosencephaly Lissencephaly Pachygyria Hydranencephaly Septo-optic dysplasia Megalencephaly CNS cyst Porencephaly Schizencephaly Polymicrogyria Bilateral frontoparietal polymicrogyria

Spinal cord

Neural tube defect	Spina bifida Rachischisis

Other	Currarino syndrome Diastomatomyelia Syringomyelia

Genetic disorder, protein biosynthesis: Transcription factor/coregulator deficiencies

(1) Basic domains

1.2	Feingold syndrome Saethre–Chotzen syndrome

1.3	Tietz syndrome

(2) Zinc finger
DNA-binding domains

2.1	(Intracellular receptor): Thyroid hormone resistance Androgen insensitivity syndrome PAIS MAIS CAIS Kennedy's disease PHA1AD pseudohypoaldosteronism Estrogen insensitivity syndrome X-linked adrenal hypoplasia congenita MODY 1 Familial partial lipodystrophy 3 SF1 XY gonadal dysgenesis

2.2	Barakat syndrome Tricho–rhino–phalangeal syndrome

2.3	Greig cephalopolysyndactyly syndrome/Pallister–Hall syndrome Denys–Drash syndrome Duane-radial ray syndrome MODY 7 MRX 89 Townes–Brocks syndrome Acrocallosal syndrome Myotonic dystrophy 2

2.5	Autoimmune polyendocrine syndrome type 1

(3) Helix-turn-helix domains

3.1	ARX Ohtahara syndrome Lissencephaly X2 MNX1 Currarino syndrome HOXD13 SPD1 Synpolydactyly PDX1 MODY 4 LMX1B Nail–patella syndrome MSX1 Tooth and nail syndrome OFC5 PITX2 Axenfeld syndrome 1 POU4F3 DFNA15 POU3F4 DFNX2 ZEB1 Posterior polymorphous corneal dystrophy Fuchs' dystrophy 3 ZEB2 Mowat–Wilson syndrome

3.2	PAX2 Papillorenal syndrome PAX3 Waardenburg syndrome 1&3 PAX4 MODY 9 PAX6 Gillespie syndrome Coloboma of optic nerve PAX8 Congenital hypothyroidism 2 PAX9 STHAG3

3.3	FOXC1 Axenfeld syndrome 3 Iridogoniodysgenesis, dominant type FOXC2 Lymphedema–distichiasis syndrome FOXE1 Bamforth–Lazarus syndrome FOXE3 Anterior segment mesenchymal dysgenesis FOXF1 ACD/MPV FOXI1 Enlarged vestibular aqueduct FOXL2 Premature ovarian failure 3 FOXP3 IPEX

3.5	IRF6 Van der Woude syndrome Popliteal pterygium syndrome

(4) β-Scaffold factors
with minor groove contacts

4.2	Hyperimmunoglobulin E syndrome

4.3	Holt–Oram syndrome Li–Fraumeni syndrome Ulnar–mammary syndrome

4.7	Campomelic dysplasia MODY 3 MODY 5 SF1 SRY XY gonadal dysgenesis Premature ovarian failure 7 SOX10 Waardenburg syndrome 4c Yemenite deaf-blind hypopigmentation syndrome

4.11	Cleidocranial dysostosis

(0) Other transcription factors

0.6	Kabuki syndrome

Ungrouped

Transcription coregulators

Coactivator:	CREBBP Rubinstein–Taybi syndrome

Corepressor:	HR (Atrichia with papular lesions)

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