U.S. flag

An official website of the United States government

Format

Send to:

Choose Destination

Links from Gene

Severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome(CCAFCA)

MedGen UID:
902346
Concept ID:
C4225193
Disease or Syndrome
Synonyms: BIRK-FLUSSER SYNDROME; Corpus callosum, agenesis of, with facial anomalies and cerebellar ataxia
SNOMED CT: Severe intellectual disability, agenesis of corpus callosum, facial dysmorphism, cerebellar ataxia syndrome (1208727002)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): FRMD4A (10p13)
 
Monarch Initiative: MONDO:0014787
OMIM®: 616819
Orphanet: ORPHA466688

Definition

A rare genetic neurological disorder with characteristics of congenital microcephaly, severe intellectual disability, hypertonia at birth lessening with age, ataxia and specific dysmorphic facial features including hirsutism, low anterior hairline and bitemporal narrowing arched thick and medially sparse eyebrows, long eyelashes, lateral upper eyelids swelling and a skin fold partially covering the inferior eyelids, low-set posteriorly rotated protruding ears, anteverted nares and a full lower lip. Brain imaging shows partial to almost complete agenesis of the corpus callosum and variable degrees of cerebellar hypoplasia. Caused by homozygous mutation in the FRMD4A gene on chromosome 10p13. [from SNOMEDCT_US]

Clinical features

From HPO
Low-set ears
MedGen UID:
65980
Concept ID:
C0239234
Congenital Abnormality
Upper insertion of the ear to the scalp below an imaginary horizontal line drawn between the inner canthi of the eye and extending posteriorly to the ear.
Posteriorly rotated ears
MedGen UID:
96566
Concept ID:
C0431478
Congenital Abnormality
A type of abnormal location of the ears in which the position of the ears is characterized by posterior rotation (the superior part of the ears is rotated towards the back of the head, and the inferior part of the ears towards the front).
Protruding ear
MedGen UID:
343309
Concept ID:
C1855285
Finding
Angle formed by the plane of the ear and the mastoid bone greater than the 97th centile for age (objective); or, outer edge of the helix more than 2 cm from the mastoid at the point of maximum distance (objective).
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Cerebellar hypoplasia
MedGen UID:
120578
Concept ID:
C0266470
Congenital Abnormality
Cerebellar hypoplasia is a descriptive term implying a cerebellum with a reduced volume, but a normal shape and is stable over time.
Partial agenesis of the corpus callosum
MedGen UID:
98127
Concept ID:
C0431368
Congenital Abnormality
A partial failure of the development of the corpus callosum.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Cerebellar vermis hypoplasia
MedGen UID:
333548
Concept ID:
C1840379
Finding
Underdevelopment of the vermis of cerebellum.
Absent speech
MedGen UID:
340737
Concept ID:
C1854882
Finding
Complete lack of development of speech and language abilities.
Aplasia/Hypoplasia of the corpus callosum
MedGen UID:
354608
Concept ID:
C1861866
Finding
Absence or underdevelopment of the corpus callosum.
Intellectual disability
MedGen UID:
811461
Concept ID:
C3714756
Mental or Behavioral Dysfunction
Intellectual disability, previously referred to as mental retardation, is characterized by subnormal intellectual functioning that occurs during the developmental period. It is defined by an IQ score below 70.
Primary microcephaly
MedGen UID:
383046
Concept ID:
C2677180
Finding
Head circumference below 2 standard deviations below the mean for age and gender at birth.
Narrow forehead
MedGen UID:
326956
Concept ID:
C1839758
Finding
Width of the forehead or distance between the frontotemporales is more than two standard deviations below the mean (objective); or apparently narrow intertemporal region (subjective).
Anteverted nares
MedGen UID:
326648
Concept ID:
C1840077
Finding
Anteriorly-facing nostrils viewed with the head in the Frankfurt horizontal and the eyes of the observer level with the eyes of the subject. This gives the appearance of an upturned nose (upturned nasal tip).
Low anterior hairline
MedGen UID:
331280
Concept ID:
C1842366
Finding
Distance between the hairline (trichion) and the glabella (the most prominent point on the frontal bone above the root of the nose), in the midline, more than two SD below the mean. Alternatively, an apparently decreased distance between the hairline and the glabella.
Everted lower lip vermilion
MedGen UID:
344003
Concept ID:
C1853246
Finding
An abnormal configuration of the lower lip such that it is turned outward i.e., everted, with the Inner aspect of the lower lip vermilion (normally opposing the teeth) being visible in a frontal view.
Thick eyebrow
MedGen UID:
377914
Concept ID:
C1853487
Finding
Increased density/number and/or increased diameter of eyebrow hairs.
Upper eyelid edema
MedGen UID:
825252
Concept ID:
C3839407
Finding
Edema in the region of the upper eyelid.
Hirsutism
MedGen UID:
42461
Concept ID:
C0019572
Disease or Syndrome
Abnormally increased hair growth referring to a male pattern of body hair (androgenic hair).
Long eyelashes
MedGen UID:
342955
Concept ID:
C1853738
Finding
Mid upper eyelash length >10 mm or increased length of the eyelashes (subjective).
Sparse hair
MedGen UID:
1790211
Concept ID:
C5551005
Finding
Reduced density of hairs.
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSevere intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome

Professional guidelines

PubMed

DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS
Mol Genet Metab 2012 Nov;107(3):394-402. Epub 2012 Sep 7 doi: 10.1016/j.ymgme.2012.09.001. PMID: 23021068

Recent clinical studies

Etiology

Fouda MA, Kim TY, Cohen AR
World Neurosurg 2022 Mar;159:48-53. Epub 2021 Dec 22 doi: 10.1016/j.wneu.2021.12.062. PMID: 34954057
Tessa A, Battini R, Rubegni A, Storti E, Marini C, Galatolo D, Pasquariello R, Santorelli FM
Eur J Neurol 2016 Oct;23(10):1580-7. Epub 2016 Jul 22 doi: 10.1111/ene.13085. PMID: 27444738
Ebrahimi-Fakhari D, Saffari A, Wahlster L, Lu J, Byrne S, Hoffmann GF, Jungbluth H, Sahin M
Brain 2016 Feb;139(Pt 2):317-37. Epub 2015 Dec 29 doi: 10.1093/brain/awv371. PMID: 26715604Free PMC Article
DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS
Mol Genet Metab 2012 Nov;107(3):394-402. Epub 2012 Sep 7 doi: 10.1016/j.ymgme.2012.09.001. PMID: 23021068
Sherr EH
Curr Opin Pediatr 2003 Dec;15(6):567-71. doi: 10.1097/00008480-200312000-00004. PMID: 14631200

Diagnosis

Fouda MA, Kim TY, Cohen AR
World Neurosurg 2022 Mar;159:48-53. Epub 2021 Dec 22 doi: 10.1016/j.wneu.2021.12.062. PMID: 34954057
Asadollahi R, Zweier M, Gogoll L, Schiffmann R, Sticht H, Steindl K, Rauch A
Eur J Med Genet 2017 Sep;60(9):451-464. Epub 2017 Jun 21 doi: 10.1016/j.ejmg.2017.06.004. PMID: 28645799
Ehmke N, Karge S, Buchmann J, Korinth D, Horn D, Reis O, Häßler F
Am J Med Genet A 2017 May;173(5):1251-1256. Epub 2017 Mar 27 doi: 10.1002/ajmg.a.38145. PMID: 28345786
Tessa A, Battini R, Rubegni A, Storti E, Marini C, Galatolo D, Pasquariello R, Santorelli FM
Eur J Neurol 2016 Oct;23(10):1580-7. Epub 2016 Jul 22 doi: 10.1111/ene.13085. PMID: 27444738
Ebrahimi-Fakhari D, Saffari A, Wahlster L, Lu J, Byrne S, Hoffmann GF, Jungbluth H, Sahin M
Brain 2016 Feb;139(Pt 2):317-37. Epub 2015 Dec 29 doi: 10.1093/brain/awv371. PMID: 26715604Free PMC Article

Prognosis

Asadollahi R, Zweier M, Gogoll L, Schiffmann R, Sticht H, Steindl K, Rauch A
Eur J Med Genet 2017 Sep;60(9):451-464. Epub 2017 Jun 21 doi: 10.1016/j.ejmg.2017.06.004. PMID: 28645799
DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS
Mol Genet Metab 2012 Nov;107(3):394-402. Epub 2012 Sep 7 doi: 10.1016/j.ymgme.2012.09.001. PMID: 23021068

Clinical prediction guides

Roychaudhury A, Lee YR, Choi TI, Thomas MG, Khan TN, Yousaf H, Skinner C, Maconachie G, Crosier M, Horak H, Constantinescu CS, Kim TY, Lee KH, Kyung JJ, Wang T, Ku B, Chodirker BN, Hammer MF, Gottlob I, Norton WHJ, Gerlai R, Kim HG, Graziano C, Pippucci T, Iovino E, Montanari F, Severi G, Toro C, Boerkoel CF, Cha HS, Choi CY, Kim S, Yoon JH, Gilmore K, Vora NL, Davis EE, Chudley AE, Schwartz CE, Kim CH
Ann Neurol 2024 Nov;96(5):914-931. Epub 2024 Jul 29 doi: 10.1002/ana.27037. PMID: 39073169Free PMC Article
Brugger M, Lauri A, Zhen Y, Gramegna LL, Zott B, Sekulić N, Fasano G, Kopajtich R, Cordeddu V, Radio FC, Mancini C, Pizzi S, Paradisi G, Zanni G, Vasco G, Carrozzo R, Palombo F, Tonon C, Lodi R, La Morgia C, Arelin M, Blechschmidt C, Finck T, Sørensen V, Kreiser K, Strobl-Wildemann G, Daum H, Michaelson-Cohen R, Ziccardi L, Zampino G, Prokisch H, Abou Jamra R, Fiorini C, Arzberger T, Winkelmann J, Caporali L, Carelli V, Stenmark H, Tartaglia M, Wagner M
Am J Hum Genet 2024 Mar 7;111(3):594-613. Epub 2024 Feb 28 doi: 10.1016/j.ajhg.2024.02.005. PMID: 38423010Free PMC Article
Kaiyrzhanov R, Rad A, Lin SJ, Bertoli-Avella A, Kallemeijn WW, Godwin A, Zaki MS, Huang K, Lau T, Petree C, Efthymiou S, Karimiani EG, Hempel M, Normand EA, Rudnik-Schöneborn S, Schatz UA, Baggelaar MP, Ilyas M, Sultan T, Alvi JR, Ganieva M, Fowler B, Aanicai R, Tayfun GA, Al Saman A, Alswaid A, Amiri N, Asilova N, Shotelersuk V, Yeetong P, Azam M, Babaei M, Monajemi GB, Mohammadi P, Samie S, Banu SH, Pinto Basto J, Kortüm F, Bauer M, Bauer P, Beetz C, Garshasbi M, Issa AH, Eyaid W, Ahmed H, Hashemi N, Hassanpour K, Herman I, Ibrohimov S, Abdul-Majeed BA, Imdad M, Isrofilov M, Kaiyal Q, Khan S, Kirmse B, Koster J, Lourenço CM, Mitani T, Moldovan O, Murphy D, Najafi M, Pehlivan D, Rocha ME, Salpietro V, Schmidts M, Shalata A, Mahroum M, Talbeya JK, Taylor RW, Vazquez D, Vetro A, Waterham HR, Zaman M, Schrader TA, Chung WK, Guerrini R, Lupski JR, Gleeson J, Suri M, Jamshidi Y, Bhatia KP, Vona B, Schrader M, Severino M, Guille M, Tate EW, Varshney GK, Houlden H, Maroofian R
Brain 2024 Apr 4;147(4):1436-1456. doi: 10.1093/brain/awad380. PMID: 37951597Free PMC Article
Asadollahi R, Zweier M, Gogoll L, Schiffmann R, Sticht H, Steindl K, Rauch A
Eur J Med Genet 2017 Sep;60(9):451-464. Epub 2017 Jun 21 doi: 10.1016/j.ejmg.2017.06.004. PMID: 28645799
DeBrosse SD, Okajima K, Zhang S, Nakouzi G, Schmotzer CL, Lusk-Kopp M, Frohnapfel MB, Grahame G, Kerr DS
Mol Genet Metab 2012 Nov;107(3):394-402. Epub 2012 Sep 7 doi: 10.1016/j.ymgme.2012.09.001. PMID: 23021068

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Recent activity

    Your browsing activity is empty.

    Activity recording is turned off.

    Turn recording back on

    See more...