Alternative titles; symbols
SNOMEDCT: 703542000; ORPHA: 1571;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 21q22.3 | Knobloch syndrome, type 1 | 267750 | Autosomal recessive | 3 | COL18A1 | 120328 |
A number sign (#) is used with this entry because Knobloch syndrome-1 (KNO1) is caused by homozygous or compound heterozygous mutation in the COL18A1 gene (120328) on chromosome 21q22.
Knobloch syndrome-1 (KNO1) is an autosomal recessive developmental disorder primarily characterized by typical eye abnormalities, including high myopia, cataracts, dislocated lens, vitreoretinal degeneration, and retinal detachment, with occipital skull defects, which can range from occipital encephalocele to occult cutis aplasia (summary by Aldahmesh et al., 2011).
Genetic Heterogeneity of Knobloch Syndrome
KNO2 (618458) is caused by mutation in the PAK2 gene (605022) on chromosome 3q29.
Knobloch and Layer (1971) reported a family in which 5 of 10 sibs had high myopia, vitreoretinal degeneration with retinal detachment, and occipital encephalocele. One of the patients also had total anomalous pulmonary venous return (106700). All the affected sibs had normal intelligence (Pagon et al., 1978). The parents were unaffected and denied consanguinity.
Czeizel et al. (1992) reported a Hungarian brother and sister with this syndrome comprising severe visual handicap with high myopia and retinal detachment with other defects, atypical occipital cephalocele, and unusual palmar creases.
Hoyme et al. (1992) and Seaver et al. (1993) reported 2 sibs with high myopia, vitreoretinal degeneration, and occipital scalp defects. Histologic examination of the scalp defects showed heterotopic neuronal tissue in both sibs. Both children had normal to above-normal intelligence. Seaver et al. (1993) suggested that congenital occipital scalp defects rather than true encephaloceles may, as is true in some cases of Meckel syndrome (249000), accompany Knobloch syndrome.
Passos-Bueno et al. (1994) reported a large consanguineous Brazilian kindred in which 12 patients had severe ocular alterations associated with a congenital occipital encephalocele. In 1 patient, CT scans showed a midline occipital bone defect 6 mm in diameter above the external occipital protuberance and the tentorial attachment. MRI in the same patient demonstrated an extracranial nodular, noncystic lesion, covered by thin skin. The lesion extended intracranially as a filamentous core 5 mm in diameter through the small cranial defect and ended at the posterior portion of the tentorial falx. The family of Passos-Bueno et al. (1994) provided the best support for autosomal recessive inheritance.
Sniderman et al. (2000) reported a 4-year-old boy with Knobloch syndrome with a defect of the anterior midline scalp with involvement of the frontal bone, as documented by CT scan.
Khaliq et al. (2007) reported a consanguineous Pakistani family in which multiple individuals had a disorder characterized by high myopia, vitreoretinal degeneration, and occipital scalp defect. Inheritance was autosomal recessive. Onset of night blindness occurred between ages 2 and 4 years and progressed to complete blindness between ages 15 and 18 years. Funduscopic examination showed choroidal sclerosis and chorioretinal atrophy. Other findings included pigmentary abnormalities, subluxation of the lens, cataract, glaucoma, phthisis bulbi, and nystagmus. Brain imaging of 3 patients did not show occipital encephalocele. In contrast to previous reports of Knobloch syndrome, no affected individuals had retinal detachment, and there were no extraocular manifestations aside from the scalp defect. Initial genomewide linkage analysis found linkage to chromosome 17q11.2 (maximum lod score of 3.40 at markers D17S1307 and D17S1166), and Khaliq et al. (2007) proposed the designation Knobloch syndrome type III (KNO3). However, on repeat analysis of this family, Joyce et al. (2010) identified a homozygous truncating mutation in the COL18A1 gene (120328.0006), indicating that this family had KNO1. The molecular results of Joyce et al. (2010) indicated that there is no evidence to support the KNO3 locus. The original mapping (Khaliq et al., 2007) used microsatellite markers, whereas the more recent mapping (Joyce et al., 2010) used high-density SNP arrays.
Aldahmesh et al. (2011) reported a 7-year-old girl, born of consanguineous Saudi parents, with Knobloch syndrome. Occipital meningocele was noted immediately after birth, but brain CT was normal. She presented at 18 months with poor vision, and physical examination showed ectopia lentis, cataract, and myopia. She later developed progressive retinal degeneration and serous retinal detachment. She had no cognitive delay, but did have fine motor delay thought to be related to her poor vision (Alkuraya, 2011). Although Aldahmesh et al. (2011) reported a homozygous variant in the ADAMTS18 gene (S179L; 607512.0001) as the cause of the disorder, Aldahmesh et al. (2013) later found aberrant splicing of the COL18A1 gene in this patient, suggesting that a deep intronic mutation in the COL18A1 gene was causative. Aldahmesh et al. (2013) concluded that the S179L variant in ADAMTS18 reported by Aldahmesh et al. (2011) was not responsible for and did not influence the Knobloch syndrome phenotype in this patient.
Hull et al. (2016) examined 12 patients from 7 families with Knobloch syndrome-1 and observed several new features, including pigment dispersion syndrome in 2 patients and unilateral glaucomatous disc cupping in 2 patients. Detailed electrophysiologic testing revealed cone-rod dysfunction in 10 patients, with some showing severely reduced or undetectable responses. Although occipital encephalocele or meningocele was present in only 3 patients, 5 had external occipital findings, ranging from soft-tissue swelling to hair abnormalities, and 1 patient had a cutaneous scalp abnormality in the absence of neuroradiologic abnormality.
Clinical Variability
Kliemann et al. (2003) described 4 cases of Knobloch syndrome and stated that 24 cases of the disorder had previously been reported. They noted that encephalocele had not been found in all patients and that the degree of myopia was variable, which indicated intra- and interfamilial variability. In the 4 cases of their study, they demonstrated the existence of neuronal migratory defects in this disorder.
Keren et al. (2007) reported 2 sibs with Knobloch syndrome who were born to consanguineous Algerian parents. The first child showed occipital meningocele at birth, horizontal nystagmus, and severe progressive myopia. She had mild facial dysmorphism with narrow face, high and large forehead, epicanthal folds, bulbous nasal tip, and temporal narrowing. Detailed eye examination showed vitreoretinal degeneration and paramacular retinal colobomas. She had retinal detachment and complete blindness at age 5 years. Brain MRI showed agenesis of the septum pellucidum, bilateral pachygyria/polymicrogyria of the entire frontal lobes, and heterotopic lesions, consistent with a neuronal migration defect. She had borderline mental delay and learning disability, which is usually not associated with the disorder. The fetus of the mother's next pregnancy showed a posterior encephalocele at 17 weeks of gestation, and the pregnancy was terminated. Examination of the fetus showed retrognathia, enlarged neck, and a meningocele with skull defect. There was also a severe cerebellar malformation with complete agenesis of the vermis and a poor differentiation of the hemispheres.
Paisan-Ruiz et al. (2009) reported 2 sisters from a small village in northern India with a complex neurologic disorder, including cognitive decline beginning around age 3 years, seizures, and adult-onset of progressive visual problems and cerebellar ataxia. The 48-year-old proband had glaucoma, lens dislocation, and retinal and corneal dystrophy. Cerebellar ataxia affected both upper and lower limbs, and she had nystagmus. She was independent for toileting and dressing. Brain MRI showed frontal polymicrogyria with severe cerebral and cerebellar atrophy. Her sister had a similar disease course. Genetic analysis identified a homozygous 2-bp deletion in the COL18A1 gene (120328.0002). The findings expanded the phenotype associated with Knobloch syndrome.
Mahajan et al. (2010) reported 2 sisters, born of unrelated El Salvadorian parents, with Knobloch syndrome confirmed by genetic analysis (3514delCT; 120328.0002). The proband was a 4-year-old girl with midline occipital soft tissue swelling and alopecia, hypotonia, and mild developmental delay. Brain MRI at 13 months showed an occipital dermal sinus tract, frontal cortical dysplasia, white matter loss, and mild ventriculomegaly. Her 7-year-old sister had had excision of a small occipital encephalocele at 1 month of age and an occipital scalp defect, but normal growth and development. Brain MRI at age 4 showed an occipital dermal sinus tract and multiple punctuate areas of high signal along the supratentorial sulci. She then developed acute lymphoblastic leukemia (ALL), pre-B type. Both girls had infantile nystagmus, high myopia, and poor vision. Ophthalmic evaluation showed vitreous sheets and attachments at the discs, syneresis, and areas of chorioretinal atrophy. One had small optic discs with peripapillary atrophy, and the other had left lens opacities. Both also had irregular white dots and lines at the vitreoretinal interface. Mahajan et al. (2010) speculated that lack of endostatin in these patients, resulting from a frameshift COL18A1 mutation, may have contributed to the development of ALL in 1 of the girls.
In 4 patients from distinct consanguineous Turkish families who presented for evaluation of symptomatic structural brain malformations, Caglayan et al. (2014) identified homozygous frameshift mutations in the COL18A1 gene. On further investigation, the patients were noted to have features of Knobloch syndrome. All 4 patients had characteristic eye findings (e.g., high myopia, vitreoretinal degeneration, retinal detachment, congenital aphakia, glaucoma) and unilateral or bilateral vision loss. Only one had a midline occipital bone defect characteristic of Knobloch syndrome. Findings on brain MRI included polymicrogyria in 3 patients and cerebellar vermian atrophy in 1. All 4 patients had 'cognitive decline.' Additional findings included an atrial septal defect in 1 patient and seizures in 3. Caglayan et al. (2014) proposed that patients who have COL18A1 mutations or are clinically diagnosed with Knobloch syndrome be investigated for potential structural brain malformations, even when encephalocele is absent.
Sertie et al. (1996) assigned the locus for Knobloch syndrome to chromosome 21q22.3 on the basis of homozygosity mapping in the Brazilian kindred described by Passos-Bueno et al. (1994). They analyzed a total of 438 polymorphic markers spread over 22 autosomes. Marker D21S171 was homozygous in all affected family members, and genotyping yielded a maximum lod score of 6.13. On the basis of observed recombinants, Sertie et al. (1996) mapped the disease gene to a 4.3-cM region. Sertie et al. (2000) further narrowed the candidate interval for KNO1 to a region of less than 245 kb, which contained 24 expressed sequence tags, including the 5-prime end of the COL18A1 gene.
The transmission pattern of KNO1 in the Brazilian family reported by Passos-Bueno et al. (1994) and Sertie et al. (2000) was consistent with autosomal recessive inheritance.
In all 12 affected members of a Brazilian family with Knobloch syndrome (Passos-Bueno et al., 1994), Sertie et al. (2000) identified a homozygous splice site mutation in the COL18A1 gene (120328.0001).
In the Hungarian brother and sister with Knobloch syndrome reported by Czeizel et al. (1992), Menzel et al. (2004) identified compound heterozygosity for 2 mutations in the COL18A1 gene (120328.0003; 120328.0004).
In 2 sibs with Knobloch syndrome, born of consanguineous Algerian parents, Keren et al. (2007) identified a homozygous splice site mutation in the COL18A1 gene (120328.0005).
Najmabadi et al. (2011) performed homozygosity mapping followed by exon enrichment and next-generation sequencing in 136 consanguineous families (over 90% Iranian and less than 10% Turkish or Arab) segregating syndromic or nonsyndromic forms of autosomal recessive intellectual disability. In a family (M175) in which first-cousin parents had 5 healthy children and 2 affected with Knobloch syndrome, they identified a causative homozygous frameshift mutation in the COL18A1 gene (120328.0007).
By whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing of 4 patients from distinct consanguineous Turkish families with structural brain malformations and some characteristic features of Knobloch syndrome, Caglayan et al. (2014) identified 3 different homozygous frameshift mutations in the COL18A1 gene, 1 of which had previously been reported. All 3 mutations were located in either the alpha-helix or the endostatin domain.
In 7 families with Knobloch syndrome, Hull et al. (2016) performed whole-exome and/or Sanger sequencing and identified mutations in the COl18A1 gene in all families.
In a 12-year-old boy and a 3-year-old girl with Knobloch syndrome from unrelated consanguineous Iranian families (KS100 and KS101), who exhibited poor vision, severe high myopia, macular hypoplasia, and generalized chorioretinal atrophy, Suri et al. (2018) sequenced the COL18A1 gene and identified homozygosity for frameshift mutations (120328.0011 and 120328.0012, respectively). Examination of 6 heterozygous carrier relatives revealed early evidence of iridocorneal angle closure (see GLCC; 618880) in 4 of them; the other 2 were relatively young, and the authors noted that COL18A1-associated angle closure appears to be a late-onset phenotype. The authors also suggested that mild presentations of angle closure might be overlooked in the context of the more severe disease of the offspring with KNO1.
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