A number sign (#) is used with this entry because cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (CEDNIK) is caused by homozygous or compound heterozygous mutation in the SNAP29 gene (604202) on chromosome 22q11.

Cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome (CEDNIK) refers to a unique constellation of clinical manifestations including global developmental delay with hypotonia, roving eye movements or nystagmus, poor motor skills, and impaired intellectual development with speech delay. More variable features include microcephaly, feeding difficulties, seizures, ocular anomalies, hearing loss, and nonspecific dysmorphic facial features. Palmoplantar keratoderma and ichthyosis or neuropathy develop in some patients. Brain magnetic resonance imaging (MRI) shows varying degrees of cerebral dysgenesis, including absence of the corpus callosum and cortical dysplasia, as well as hypomyelination, white matter loss, and white matter signal anomalies suggestive of a leukodystrophy. Some patients may show developmental regression; many die in childhood (Fuchs-Telem et al., 2011; Mah-Som et al., 2021). With more patients being reported, several authors (Diggle et al., 2017; Llaci et al., 2019; Mah-Som et al., 2021) have observed that the dermatologic features and peripheral neuropathy show reduced penetrance and are more variable manifestations of this disorder, as they are not observed in all patients with biallelic SNAP29 mutations.

Sprecher et al. (2005) described a clinical syndrome in 7 individuals from 2 unrelated consanguineous Arab Muslim families living in northern Israel. After a normal birth, the patients presented during the first 4 months of life with failure to thrive, roving eye movements, and poor head and trunk control. All patients had progressive microcephaly and facial dysmorphism consisting of elongated facies, downward-slanting palpebral fissures, mild hypertelorism, and flat, broad nasal root. Palmoplantar keratosis and ichthyosis appeared between 5 and 11 months of age. By 8 to 15 months, major developmental milestones were not achieved, and all patients had severe psychomotor retardation. Other features included hypoplastic optic discs and sensorineural deafness. MRI showed defects of the corpus callosum and cortical dysplasia with pachygyria and polymicrogyria. Skin biopsy showed clear vesicles in the spinous, granular, and stratum corneum layers, with retained glucosylceramides, suggesting abnormal lamellar granule maturation. Sprecher et al. (2005) concluded that this neurocutaneous syndrome results from abnormal vesicle trafficking, vesicle maturation, and vesicle fusion.

Fuchs-Telem et al. (2011) reported a brother and sister from a consanguineous Pakistani family who both required neonatal tube feeding and had dysmorphic facies with small fontanels, long pointed nose, and small chin, as well as ichthyosis, palmoplantar keratoderma, hearing loss, and severe developmental delay. Brain MRI revealed a small corpus callosum in both sibs as well as other abnormalities, including ventricular asymmetry and frontal cortical dysplasia in the sister and perisylvian polymicrogyria with extensive cortical malformation in the brother.

Ben-Salem et al. (2015) reported 2 sisters, born of consanguineous Jordanian parents, who had typical features of CEDNIK syndrome, including ichthyosis, keratoderma, dysmorphic features, and global developmental delay. However, unlike previously reported patients, both sisters presented with a collodion phenotype at birth that evolved into generalized ichthyosis, and they did not have microcephaly, cortical abnormalities, or sensorineural deafness. In addition, they had peripheral camptodactyly, which had not previously been described in this disorder.

Mah-Som et al. (2021) reported 5 patients (P1-P5) from 4 unrelated families with CEDNIK syndrome. The families were of Amish/Mennonite, Hispanic Mexican, Tibetan/Indian, and Arab descent; 3 of the families were consanguineous. The patients, who ranged from 4 to 19 years of age, demonstrated hypotonia and global developmental delay from infancy. Several patients had feeding difficulties, sometimes requiring tube feeding, failure to thrive, and constipation. A few patients had respiratory infections. They had delayed walking or inability to walk, peripheral spasticity with brisk reflexes and lower extremity clonus, and impaired intellectual development. Speech was delayed or absent, and often dysarthric. Two patients (P1 and P5) demonstrated a loss of developmental skills at 12 and 7 years of age, respectively. Three patients developed early-onset seizures that could be controlled or remitted spontaneously. All had variable ocular anomalies, including roving eye movements, nystagmus, strabismus, hyperopia, and myopia. Two patients had hearing loss, including 1 with cortical visual impairment (P4). Brain imaging showed abnormalities of the corpus callosum in 4, polymicrogyria in 2, and supratentorial hypomyelination in 3. The authors noted T1 hypointensities/T2 hyperintensities characteristic of white matter disease possibly due to defects in the myelin sheath. All had ichthyosis and 3 had keratoderma. More variable features included early puberty in 2 female patients, scoliosis in 2, and microcephaly in 2. Dysmorphic facial features were common, although a common gestalt was not apparent. Features included round face, hypotelorism, hypertelorism, deep-set eyes, bitemporal narrowing, thick eyebrows, epicanthal folds, anteverted nares, bulbous nasal tip, low-set ears, short philtrum, micrognathia, and high-arched palate. The authors noted that the 19-year-old patient may represent the oldest recorded patient to have the disorder. Mah-Som et al. (2021) also observed reduced penetrance for the skin phenotype, cerebral dysgenesis, and neuropathy, and suggested renaming the syndrome 'SNAP29-related disorder.'

Nanda et al. (2022) reported a 1.5-year-old Syrian girl, born of a highly consanguineous family, who had hypotonia, roving eye movements, nystagmus, and generalized skin erythema and scaling. She showed global developmental delay, was not able to sit or stand, and could not follow verbal commands. She had poor overall growth with small head circumference and dysmorphic features, including frontal bossing, hypertelorism, flat nasal bridge, bushy eyelashes, and low-set ears. Other findings included optic nerve hypoplasia and dysgenesis of the corpus callosum. Her younger sister was similarly affected; brain imaging in the sister showed dysplastic corpus callosum and colpocephaly. Neither patient had palmoplantar keratoderma, although 1 had a verrucous venous malformation. Family history was significant for a maternal uncle who died of the disease at 11 years of age.

Clinical Variability

Abdollahi et al. (2009) reported 2 unrelated consanguineous Pakistani families in which 4 children had severe developmental delay, hypotonia, and seizures. All had optic nerve hypoplasia and extensive polymicrogyria, with a dysplastic or absent corpus callosum and colpocephaly. There was also a distinctive abnormality of the brainstem with loss of demarcation between the pons and medulla. There were no dysmorphic features. One child died at age 2 years from an overwhelming respiratory infection, whereas the others survived with profound neurologic impairment. Diggle et al. (2017) noted that dysmorphic features, dermatologic features, and peripheral neuropathy were not observed in these patients, suggesting that these may be variable manifestations.

Llaci et al. (2019) reported a 12-year-old boy with a history of hypotonia, poor visual fixation, mild optic atrophy, and horizontal pendular nystagmus apparent from infancy. He had developmental delay with poor motor skills due to axial hypotonia and brisk reflexes with extensor plantar responses. He made steady progress and was able to manipulate a wheelchair and stand for a few steps by 6.5 years of age. Speech was severely limited. Brain imaging showed absent splenium of the corpus callosum and severely delayed myelination in the cerebral white matter, suggestive of a hypomyelinating leukodystrophy. Neuropathy was not noted. He also did not have ichthyosis or keratoderma, although he had acne, dry skin, and some verruca papules (warts). The report expanded the phenotypic spectrum resulting from biallelic mutations in the SNAP29 gene.

The transmission pattern of CEDNIK in the families reported by Mah-Som et al. (2021) was consistent with autosomal recessive inheritance.

By linkage analysis of families with CEDNIK syndrome, Sprecher et al. (2005) mapped the disorder to a 4-Mb region on chromosome 22q11.2 (maximum multipoint lod score of 4.85 at D22S446).

In 7 patients from an consanguineous Arab family with CEDNIK syndrome, Sprecher et al. (2005) identified a homozygous 1-bp deletion in the SNAP29 gene (c.220delG; 604202.0001).

In a brother and sister from a consanguineous Pakistani family who had features consistent with CEDNIK syndrome, Fuchs-Telem et al. (2011) identified homozygosity for a 1-bp insertion in the SNAP29 gene (c.486insA; 604202.0002) that was not found in 200 control chromosomes. DNA from other family members was not available.

Although initial studies by Abdollahi et al. (2009) identified a homozygous deletion in the TUBA8 gene (605742.0001) in 4 Pakistani children with brain abnormalities, reanalysis of these patients by Diggle et al. (2017) identified a homozygous frameshift mutation in the SNAP29 gene (604202.0002). Diggle et al. (2017) concluded that the SNAP29 mutation was likely responsible for the phenotype in these patients.

In 2 sisters, born to consanguineous Jordanian parents, with CEDNIK syndrome, Ben-Salem et al. (2015) identified homozygosity for the same c.220delG mutation that had previously been identified in affected members of an Arab family by Sprecher et al. (2005), suggesting a founder mutation.

In a 12-year-old boy of Caucasian/Hispanic descent with a variant of CEDNIK, Llaci et al. (2019) identified compound heterozygous mutations in the SNAP29 gene (604202.0003 and 604202.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. SNAP29 expression was significantly lower in the patient's blood cells compared to controls. Western blot analysis of patient fibroblasts showed an absence of the full-length protein. These findings were consistent with a loss of function, although additional functional studies were not performed.

In 5 patients from 4 unrelated families with CEDNIK, Mah-Som et al. (2021) identified homozygous putative loss-of-function mutations in the SNAP29 gene (see, e.g., 604202.0003-604202.0005). The mutations, which were found by various genetic sequencing techniques, segregated with the disorder in the families. There were 2 frameshift and 1 nonsense mutations, as well as a mutation that interrupted the initiation codon. Functional studies of the variants and studies of patient cells were not performed.

In 2 sisters, born of consanguineous Syrian parents, with CEDNIK, Nanda et al. (2022) identified a homozygous frameshift mutation in the SNAP29 gene (604202.0001). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed.