A number sign (#) is used with this entry because of evidence that craniolenticulosutural dysplasia (CLSD) is caused by homozygous or heterozygous mutation in the SEC23A gene (610511) on chromosome 14q21.

Craniolenticulosutural dysplasia is characterized by facial dysmorphism, late-closing fontanels, cataract, and skeletal defects (summary by Boyadjiev et al., 2011).

Boyadjiev et al. (2003) suggested the designation craniolenticulosutural dysplasia (CLSD) for a dysmorphic syndrome in 5 males and 1 female in an inbred Saudi Arabian family. The craniofacial features included wide open calvarial sutures with large and late-closing anterior fontanels, frontal bossing, hyperpigmentation with capillary hemangioma of the forehead, significant hypertelorism, and a broad and prominent nose. All affected individuals had Y-shaped sutural cataracts diagnosed by 1 to 2 years of age.

Boyadjiev et al. (2011) reported a 4.5-year-old boy with CLSD who had a characteristic facial appearance as well as clinical and skeletal features similar to those of the original patients described by Boyadjiev et al. (2003). Facial features common to all CLSD patients included high and prominent forehead with increased vascular markings in the area of the open anterior fontanel, similar shape of the eyebrows, obvious hypertelorism, wide and prominent nasal ridge, and anteverted nares, with lateral skull x-rays documenting large and hypomineralized calvaria in the area of the anterior fontanel. However, the eye phenotypes differed, with esotropia, bilateral optic atrophy, and double-ring sign of the lens present in the new case, but no cataract detected by 4.5 years of age. Other previously undescribed features included macrocephaly, anterior frenulum linguae requiring frenulectomy, bifid uvula, cleft palate, gastroesophageal reflux with postnatal failure to thrive, valvular pulmonic stenosis, and osteopenia.

Cisarova et al. (2022) reported a father and son with CLSD and mutation in the SEC23A gene. Facial dysmorphism and large cranial defects were noticed at birth in the boy. Examination at age 2 months showed large fontanels with wide cranial sutures, large forehead, hypertelorism, thin nose, high-arched palate, and micrognathia. On follow-up at 18 months, the anterior fontanel was still wide and the sagittal suture was open. Length, weight, and head circumference were all at the lower limits of the normal range. Ophthalmologic examination was normal. His father, who exhibited a large forehead, hypertelorism, and thin beaked nose, had a history of large fontanels in childhood, which only closed around age 10 years. The father had undergone surgery for bilateral glaucoma, at which time bilateral embryotoxon and exfoliation of the lens capsule were noted. Skull x-rays showed that fontanels and sutures were closed, but he lacked development of the frontal sinuses. The father had a mild learning disability but psychomotor development was normal in the son.

The transmission pattern of CLSD in the family reported by Boyadjiev et al. (2006) was consistent with autosomal recessive inheritance.

The transmission pattern of CLSD in the family reported by Cisarova et al. (2022) was consistent with autosomal dominant inheritance.

By a genomewide scan, Boyadjiev et al. (2003) found linkage of craniolenticulosutural dysplasia in a Saudi Arabian family to chromosome 14q13-q21; the maximum 2-point lod score, assuming recessive inheritance, was 4.58 at theta = 0.0 with marker GATA126A04. Haplotype analysis narrowed the disease locus to a region of approximately 7.26 Mb.

In affected members of a Saudi Arabian family with CLSD, Boyadjiev et al. (2006) identified a homozygous missense mutation in the SEC23A gene (F382L; 610511.0001). SEC23A is an essential component of the COPII-coated vesicles that transport secretory proteins from the endoplasmic reticulum to the Golgi complex. In fibroblasts from individuals affected with CLSD, a gross dilatation of the endoplasmic reticulum was demonstrated by electron microscopy and immunofluorescence. These cells also exhibited cytoplasmic mislocalization of SEC31 (see 610257).

In a 4.5-year-old boy with CLSD, Boyadjiev et al. (2011) identified heterozygosity for a paternally inherited missense mutation in the SEC23A gene (M702V; 610511.0002); no mutations were identified in the coding region or 5-prime or 3-prime UTR of maternal SEC23A, and SNP and RT-PCR analysis excluded deletion of the maternal allele. Cultured skin fibroblasts from the patient showed a severe secretion defect of collagen with enlarged endoplasmic reticulum (ER); milder collagen secretion defects and ER distention were present in fibroblasts from the clinically unaffected father, indicating that an additional mutation was present in the proband. Boyadjiev et al. (2011) suggested that digenic inheritance might be involved in CLSD; RT-PCR DNA sequencing of the SEC23B (610512), SEC31A, and SEC13 (600152) genes revealed no mutations.

By trio genome analysis in a father and son with CLSD and the unaffected mother, Cisarova et al. (2022) identified heterozygosity for a missense mutation in the SEC23A gene (E599K; 610511.0003) that segregated with disease in the family and was not found in public variant databases. The paternal grandparents did not carry the mutation, indicating that it arose de novo in the proband's father. Analysis of the SEC23A gene did not reveal further pathogenic variants, and bioinformatic analysis of genome data for variants shared by the father and son and absent in the unaffected mother did not reveal variants in any gene known to interact with SEC23A. The authors suggested that the E599K variant might have a dominant-negative effect, but functional studies were not done.

Exclusion Studies

Boyadjiev et al. (2003) performed sequence analysis of the PAX9 gene (167416) in members of the Saudi Arabian family with CLSD and found no mutations.