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).

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.

Other skeletal abnormalities include shortness of the limbs, epiphyseal dysplasia, multiple joint dislocations, tibial agenesis, or brachymesophalangy (Sueldo and Fernandes 1993; 25; 15). With age, patient may develop kyphoscoliosis.

Neuroradiologic anomalies. Agenesis or hypogenesis of corpus callosum is considered a cardinal feature. Interestingly, 2 patients with KIF7 mutations did not display callosal anomalies (15). 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 and/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 (20; 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 (22; 10; 15).

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; 15).

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.

Biological basis

Etiology and pathogenesis

KIF7, the human ortholog of Drosophila Costal2, encodes a ciliary protein and is a key regulator of sonic hedgehog (SHH) signaling pathway through regulation and processing of GLI transcription factors, by preventing an inappropriate activation of Gli2, and as a positive regulator by preventing the processing of Gli3 into its repressor form (16). KIF7 is essential for maintaining Golgi structure and regulating microtubule acetylation and stabilization, which could explain cilia anomalies observed in the loss of KIF7 function (07).

Homozygous Kif7 mutant mouse embryos, as well as human acrocallosal syndrome patients, show a decrease in Gli3R levels, leading to ectopic derepression of Gli3 target genes and to a polydactyly phenotype. Macrocephaly and facial widening are likely caused by abnormal ciliary signaling response to the SHH morphogen gradient (03).

Heterozygous mutations in the KIF7 gene were identified in patients with other ciliopathies such as Bardet-Biedl syndrome, Meckel syndrome, Pallister-Hall syndrome, and orofaciodigital 6, suggesting a modifier effect of KIF7 variations (16).

A homozygous missense mutation was reported in a family with associating features of acrocallosal syndrome and multiple epiphyseal dysplasia (01). It is noteworthy that there is no genotype-phenotype correlation to explain hydrolethalus syndrome—the extreme phenotype of acrocallosal syndrome.

Epidemiology

The incidence and prevalence of acrocallosal syndrome are yet to be determined. Fewer than 50 cases have been reported, and many of them are located around the Mediterranean basin. Thus, it was proposed to be higher in that area (15; 04; 03).

Prevention

Genetic counseling. Agenesis of the corpus callosum and polydactyly could be detected early by prenatal ultrasound. Acrocallosal syndrome should be considered in the differential diagnosis and genetic testing of K1F7 and or GLI3 gene mutations will confirm the diagnosis.

After having an affected child with biallelic K1F7, couples are considered to be at high risk of being heterozygote carriers for acrocallosal syndrome and are given a 25% risk of recurrence for each subsequent pregnancy. In contrast, the reported GLI3 mutations are de novo, thus minimal recurrence risk. Genetic testing is crucial in genetic counseling, carrier detection, and family planning (21).

Differential diagnosis

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 (23).

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 (14). 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 Joubert syndrome patients 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).

Diagnostic workup

The presence of macrocephaly and distal limb anomalies should attract the attention towards acrocallosal syndrome.

Management

Rehabilitation. No specific treatment is available but symptomatic treatment.

Special considerations

Pregnancy

No information is found about increased risk for reproductive failure or for premature or abnormal delivery in heterozygote carriers for the acrocallosal syndrome gene. Decreased fetal movements have been reported in some cases.

Anesthesia

Cleft and/or high arched palate and micrognathia could make the airway manipulation difficult in children with acrocallosal syndrome. Laryngeal mask airway was advised to be adequate for airway control with spontaneous or controlled mechanical ventilation in these patients and can be recommended when difficult tracheal intubation is anticipated. Thiopental or ketamine for the induction and sevoflurane with a remifentanil infusion for the maintenance of anesthesia proved effective in 1 case (02).