Acrocallosal syndrome

David J Harris MD

Developmental Malformations

Updated 07.02.2024
Released 07.17.1995
Expires For CME 07.02.2027

Acrocallosal syndrome

Author: David J Harris MD

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Editor: Ganeshwaran H Mochida MD

Acrocallosal syndrome

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Introduction

Overview

Acrocallosal syndrome (ACLS) is a multiple congenital abnormalities/intellectual disability syndrome. The clinical diagnosis is based on the presence of three of the four major criteria: (1) macrocephaly and facial dysmorphism, (2) partial or total agenesis of corpus callosum, (3) distal limb anomalies, and (4) intellectual disability. Biallelic mutations of the K1F7 gene would confirm the clinical diagnosis as it was implicated in typical acrocallosal syndrome. Further, a phenotype consistent with acrocallosal syndrome was identified in two patients harboring de novo/dominant mutations in GLI3. The phenotypic spectrum includes a severe form with in utero fetal death known as hydrolethalus-2 syndrome usually presenting with hydrocephalus or anencephaly. This clinical variability can be explained by the action of K1F7, as it is a regulator of the Sonic Hedgehog pathway by preventing an inappropriate activation of Gli2 and the processing of Gli3 into its repressor form. The clinical spectrum of acrocallosal syndrome and differential diagnoses are discussed.

Key points

	• Acrocallosal syndrome is a ciliopathy disorder typically characterized by macrocephaly, agenesis/hypogenesis of corpus callosum, polydactyly, and intellectual disability.
	• Hydrolethalus-2 is a more severe phenotype, including death in utero.
	• Biallelic mutations in K1F7 gene are the most common mutations implicated in acrocallosal syndrome.
	• De novo mutations in the GLI3 gene were identified in a few cases with acrocallosal syndrome (20).

Historical note and terminology

Acrocallosal syndrome (ACLS) was first recognized by Schinzel in two separate publications of two unrelated Swiss patients with macrocephaly, agenesis of the corpus callosum, hypertelorism, and polydactyly and was termed because of the unique association of corpus callosum and distal acral anomalies most commonly pre and/or postaxial polydactyly (18; 19). Biallelic mutations in KIF7 are delineated in the majority of patients, thus, autosomal recessive mode of inheritance. The phenotype is ranging from the lethal anencephaly to a previously unrecognized mild end of the spectrum. In contrast, de novo heterozygous GLI3 mutations were reported in two unrelated patients with acrocallosal syndrome. The exact frequency of acrocallosal syndrome is difficult to determine. The clinical spectrum has been broadened not only to include hypogenesis/agenesis of corpus callosum but also cystic malformation of the brain (25; 13). Midline defects such as cleft palate or congenital heart defects have been reported. Furthermore, anophthalmia, lack of nasal structures, and omphalocele have been described (06). Nevertheless, hypogenitalism was noted in few patients (23; 10; 16).

Clinical manifestations

Presentation and course

Diagnosis of the acrocallosal syndrome is based on the observation of macrocephaly, facial dysmorphism, preaxial and postaxial polydactyly of hands and feet, mental retardation, and partial or total agenesis of the corpus callosum.

Craniofacial features. Craniofacial features include macrocephaly, large anterior fontanelle, frontal bossing, broad and prominent forehead, hypertelorism, depressed/wide nasal bridge, short nasolabial distance with a short and protruding upper lip, high or cleft palate, and low-set ears with notched or creased lobules. No ocular motor apraxia was noted. With age, the facial dysmorphism became more severe (03).

Craniofacial dysmorphisms

Brothers ages 4 and 6 years with acrocallosal syndrome. Note the hypertelorism, small nasal bridge, and wide, prominent forehead. The upper lip protrudes. The ears are low set. (Contributed by Dr. Gelman-Kohan.)

Interestingly, anencephaly was noted in siblings with acrocallosal syndrome, suggesting that anencephaly could be the severe type of acrocallosal syndrome (12).

Limb anomalies. Most often postaxial polydactyly type A (well-formed extra digit) or type B (pedunculated postminimi) is observed in the hands and feet associated to preaxial polysyndactyly of the feet. The severity varies, ranging from a broad first toe to a complete duplication of all the structures.

Polydactyly in acrocallosal syndrome

Polydactyly of the feet and duplication of the great toe in acrocallosal syndrome. (Contributed by Dr. Gelman-Kohan.)
Polydactyly in acrocallosal syndrome (roentgenogram)

Plain roentgenogram of a patient with acrocallosal syndrome demonstrates duplication of phalangeal bones and one extra poorly formed metatarsal of the duplicated hallux. (Contributed by Dr. Gelman-Kohan.)

Other skeletal abnormalities include shortness of the limbs, epiphyseal dysplasia, multiple joint dislocations, tibial agenesis, or brachymesophalangy (Sueldo and Fernandes 1993; 26; 16). With age, patient may develop kyphoscoliosis.

Neuroradiologic anomalies. Agenesis or hypogenesis of corpus callosum is considered a cardinal feature. Interestingly, two patients with KIF7 mutations did not display callosal anomalies (16). In addition, ventriculomegaly and hypoplastic cerebellar vermis presenting with molar tooth sign are the main neuroradiologic anomalies. Intracerebral cysts were found in 20% of patients and may be a useful diagnostic feature. The walls of these cysts consist of epidermal or choroid plexus cells, indicating abnormal cerebral ventricle development. Cerebellar or brainstem hypoplasia, (09), polymicrogyria (05), pachygyria (Sueldo and Fernandes 1993; 09), and heterotopias (13; 08) were also reported in individual cases (13).

Developmental delay and intellectual disability. The majority of patients display moderate to severe intellectual disability that is persistent with age. However, mild intellectual disability was reported in few patients. Further, autism was described in a boy with acrocallosal syndrome may be coincidental (21; 03).

Cardiovascular anomalies. Cardiovascular anomalies include abnormal configuration of the ventricles or tetralogy of Fallot.

Urogenital anomalies. Urogenital anomalies include micropenis, cryptorchidism, hypospadias, renal cysts, rectovaginal fistula, and imperforated anus (23; 10; 16).

Other features. Neonatal hypotonia, cyanotic and apneic spells, repeated infection, umbilical and inguinal hernias, high myopia, diabetes insipidus, hypothyroidism, and malignant hyperthermia have been listed among the less frequently observed associated anomalies (10; 16).

Prognosis and complications

Acrocallosal syndrome is a nonprogressive disorder. Adults of acrocallosal syndrome did not show catch up or improvement of the degree of intellectual disability with age. Aggressive behavior and high myopia are common.

Differential diagnosis

Confusing conditions

OFD1 is an X-linked dominant characterized by facial anomalies and characteristic abnormalities in oral cavity (cleft palate, bifid/lobulated tongue, tongue hamartoma, oral frenula, and lip notch) and postaxial polydactyly. Renal cystic disease is reported in the majority of cases. Furthermore, corpus callosum defects (agenesis or hypoplasia, ACC), arachnoid cysts, neuronal migration/organization disorders, and cerebellar developmental anomalies are common findings. Congenital heart defects, genitourinary malformations, and ophthalmological abnormalities have been reported. It is caused by mutations in OFD1 (24).

Simpson-Golabi-Behmel syndrome type 2 is an X-linked recessive genetic disorder characterized by advance bone age and dysmorphic facial features including macrocephaly, low-set posteriorly, angulated ears, hypertelorism, short and broad nose with anteverted nares, large mouth with thin upper vermilion border, prominent philtrum, high arched or cleft palate, and short neck.

Pallister-Hall syndrome is an autosomal dominant genetic disorder characterized mainly by mesoaxial polydactyly and hypothalamic hamartoma. Other features include Y-shaped central metacarpal/metatarsal, concurrent postaxial polydactyly, bifid epiglottis, imperforate anus, renal abnormalities, and genital defects. It is caused by heterozygous mutations of the GLI3 gene.

Joubert syndrome is a heterogeneous autosomal recessive disorder characterized by a specific congenital malformation of the hindbrain called molar tooth sign. Ocular motor apraxia is very characteristic in Joubert syndrome. Renal and retinal anomalies or postaxial polydactyly are common, whereas corpus callosum agenesis is rare in Joubert syndrome, and renal and retinal anomalies are absent in acrocallosal syndrome (15). To date, more than 27 causative genes have been identified in Joubert syndrome and related disorders. Mutations in KIF7 were identified as causative for Joubert syndrome type 12 in a consanguineous Egyptian family (07). It is noteworthy to mention that patients with Joubert syndrome harboring biallelic C5orf42 mutations show craniofacial similarity to acrocallosal syndrome, suggesting its functional link to KIF7 through SHH signaling.

Greig cephalopolysyndactyly syndrome is an autosomal dominant genetic disorder caused by heterozygous mutations/deletion resulting in haploinsufficiency of the GLI3 gene. Craniofacial abnormalities, which are generally mild, include hypertelorism and a high forehead. Preaxial polydactyly is a constant feature in Greig cephalopolysyndactyly syndrome, but half of the cases lack hypertelorism (11). Agenesis of corpus callosum is not detected in all patients with Greig cephalopolysyndactyly syndrome. Furthermore, macrocephaly could be used as a criterion to distinguish Greig cephalopolysyndactyly syndrome from acrocallosal syndrome being more prevalent in the later.

Macrocephaly is an autosomal recessive disorder characterized by distinctive facial features including macrocephaly, frontal bossing, depressed nasal bridge, and low set ears. This is associated with absent/hypoplastic corpus callosum and multiple epiphyseal dysplasia. This picture is caused by missense homozygous mutation in KIF7 (01).

Media

References

01: Ali BR, Silhavy JL, Akawi NA, Gleeson JG, Al-Gazali L. A mutation in KIF7 is responsible for the autosomal recessive syndrome of macrocephaly, multiple epiphyseal dysplasia and distinctive facial appearance. Orphanet J Rare Dis 2012;7-27. PMID 22587682
02: Aliki S, Theodosia V, Apostolos A, Andreas M, Christos I. Anesthetic management of a child with acrocallosal syndrome. Paediatr Anaesth 2008;18(10):1001-2. PMID 18811850
03: Asadollahi R, Strauss JE, Zenker M, et al. Clinical and experimental evidence suggest a link between KIF7 and C5orf42-related ciliopathies through Sonic Hedgehog signaling. Eur J Hum Genet 2018;26(2):197-209. PMID 29321670
04: Barakeh D, Faqeih E, Anazi S, et al. The many faces of KIF7. Hum Genom Variat 2015;15006. Available at http://www.nature.com/articles/hgv20156. Accessed June 2015.
05: Casamassima AC, Beneck D, Gewitz MH, et al. Acrocallosal syndrome: additional manifestations. Am J Med Genet 1989;32(3):311-7. PMID 2658584
06: Christensen B, Blaas HG, Isaksen CV, Roald B, Orstavik KH. Sibs with anencephaly, anophthalmia, clefts, omphalocele, and polydactyly: hydrolethalus or acrocallosal syndrome. Am J Med Genet 2000;91:231-4. PMID 10756349
07: Dafinger C, Liebau MC, Elsayed SM, et al. Mutations in KIF7 link Joubert syndrome with Sonic Hedgehog signaling and microtubule dynamics. J Clin Invest 2011;121(7):2662-7. PMID 21633164
08: Fernandez C, Soulier M, Coulibaly B, et al. Acrocallosal syndrome in fetus: focus on additional brain abnormalities. Acta Neuropathol 2008;115(1):151-6. PMID 17593378
09: Gul D, Ulucan H, Unay B, Akin R, Gokcay E. Acrocallosal syndrome: report of five Turkish patients. Clin Dysmorphol 2004;13(4):241-6. PMID 15365461
10: Ikbal M, Tastekin A, Ors R. Micropenis in a newborn with acrocallosal syndrome. Genet Couns 2004;15(2):233-5. PMID 15287426
11: Johnston JJ, Olivos-Glander I, Turner J, et al. Clinical and molecular delineation of the Greig cephalopolysyndactyly contiguous gene deletion syndrome and distinction from acrocallosal syndrome. Am J Med Genet A 2003;123(3);236-42. PMID 14608643
12: Kedar I, Amiel A, Fejgin M, Drugan A. Recurrent anencephaly as a primary manifestation of the acrocallosal syndrome. Am J Med Genet 1996;62:415-6. PMID 8723075
13: Koenig R, Bach A, Woelki U, Grzeschik KH, Fuchs S. Spectrum of the acrocallosal syndrome. Am J Med Genet 2002;108:7-11. PMID 11857542
14: Niida Y, Togi S, Ura H. Molecular bases of human malformation syndromes involving the SHH pathway: GLIA/R balance and cardinal phenotypes. Int J Mol Sci 2021;22(23):13060. PMID 34884862
15: Parisi MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet 2009;151C(4):326-40. PMID 19876931
16: Putoux A, Nampoothiri S, Laurent N, et al. Novel KIF7 mutations extend the phenotypic spectrum of acrocallosal syndrome. J Med Genet 2012;49(11):713-20. PMID 23125460
17: Putoux A, Thomas S, Coene KL, et al. K1F7mutations cause fetal hydrolethalus and acrocallosal syndromes. Nat Genet 2011;43(6):601-6. PMID 21552264
18: Schinzel A. Postaxial polydactyly, hallux duplication, absence of the corpus callosum, macrencephaly and severe mental retardation: a new syndrome. Helv Paediatr Acta 1979;34:141-6. PMID 457430
19: Schinzel A, Schmid W. Hallux duplication, postaxial polydactyly, absence of the corpus callosum, severe mental retardation, and additional anomalies in two unrelated patients: a new syndrome. Am J Med Genet 1980;6:241-9. PMID 7424976
20: Speksnijder L, Cohen-Overbeek TE, Knapen MF, et al. A de novo GLI3 mutation in a patient with acrocallosal syndrome. Am J Med Genet 2013;161(6):1394-400. PMID 23633388
21: Steiner CE, Guerreiro MM, Marques-de-Faria AP. Brief report: acrocallosal syndrome and autism. J Autism Dev Disord 2004;34(6):723-6. PMID 15679191
22: Tastekin A, Ingec M, Onbas O, et al. Antenatally diagnosed acrocallosal syndrome with intact corpus callosum: second affected offspring. Genet Couns 2005;16(4):425-8. PMID 16440888
23: Temtamy SA, Meguid NA. Hypogenitalism in the acrocallosal syndrome. Am J MedGenet 1989;32:301-5. PMID 2658583
24: Thauvin-Robinet C, Cossee M, Cormier-Daire V, et al. Clinical, molecular, and genotype-phenotype correlation studies from 25 cases of oral-facial-digital syndrome type 1: a French and Belgian collaborative study. J Med Genet 2006;43(1):54-61. PMID 16397067
25: Thyen U, Aksu F, Bartsch O, Herb E. Acrocallosal syndrome: association with cystic malformation of the brain and neurodevelopmental aspects. Neuropediatrics 1992;23:292-6. PMID 1491747
26: Verloes A. Severe acrocallosal syndrome or acromelic frontonasal dysplasia. Am J Med Genet 1994;50:306. PMID 8080574

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

David J Harris MD

Dr. Harris of Yale University has no relevant financial relationships to disclose.
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Editor

Ganeshwaran H Mochida MD

Dr. Mochida of Boston Children's Hospital and Harvard Medical School has no relevant financial relationships to disclose.
See Profile

Former Authors

Zully Gelman-Kohan MD
Ghada M H Abdel-Salam MD
Harvey B Sarnat MS MD FRCPC

Patient Profile

Age range of presentation: 0 to 01 month
Sex preponderance: Skewed sex ratio: male>female
Heredity: Autosomal dominant

autosomal recessive
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

ICD & OMIM codes

ICD-10: Multiple congenital malformations, not elsewhere classified: 89.7

Other specified syndromes with multiple structural anomalies, not of environmental origin: LD2F.1Y
OMIM: Acrocallosal syndrome: #200990

OFD1: #311200

Simpson-Golabi-Behmel syndrome type 2: #300170

Pallister-Hall syndrome: #146510

Joubert syndrome: #213300

Greig cephalopolysyndactyly syndrome: #175700

Macrocephaly: #248000

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Acrocallosal syndrome

Associated Disorders

Congenital cardiovascular anomalies
Diabetes mellitus
Hypogenitalism

Differential Diagnosis

Greig cephalopolysyndactyly syndrome
orofaciodigital syndrome

Also Relevant

Agenesis of the corpus callosum
Anencephaly
Intellectual disability

Clinical Categories

Developmental Malformations

	• Cardiorespiratory monitor for cyanotic or apneic spells. Caffeine or supplementary oxygen could be used as stimulatory medications, particularly in the newborn period.
	• Cleft palate should be corrected.
	• In patients with high myopia, correction of vision should be considered.
	• Plastic surgery is indicated if the number of extra digits affects the function or comfort of the patient.
	• Seizures control seems to be easy to obtain with standard antiepileptic drugs.
	• Early intervention, special developmental stimulation, and follow-up should be encouraged.

Acrocallosal syndrome

Acrocallosal syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

Acrocallosal syndrome

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Special considerations

Pregnancy

Anesthesia

Media

References

Contributors

Author

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

X-linked hydrocephalus (L1 syndrome)

Cerebro-oculo-facio-skeletal syndrome

Schizencephaly

Fetal anticonvulsant syndrome

Rhombencephalosynapsis

Malformations of the brain

Von Hippel-Lindau disease

Vein of Galen malformations

This is an article preview.
Start a Free Account
to access the full version.