Background
Knobloch Syndrome (KS) is a rare autosomal recessive syndrome first described in 1971 characterized by vitreoretinal degeneration and occipital skull abnormalities [
1]. Clinical heterogeneity is present, although virtually all patients have ocular abnormalities that typically result in bilateral loss of vision. Ophthalmic findings include retinal detachment (RD), high myopia, early-onset cataracts, pigment dispersion, congenital glaucoma, and lens subluxation.
Midline occipital defects, namely bone defects, encephalocele, or aplasia cutis congenita, are characteristic findings. Other central nervous system findings are overall rare and not considered to be stereotypic features of KS. Caglayan et al. review seven cases of patients with KS associated with other central nervous system findings including pachygyria, polymicrogyria and cerebellar atrophy among other findings [
2]. Developmental delay is observed in only a minority of patients, although is observed more frequently in patients who also possess central nervous system abnormalities [
2,
3]. Other less common findings include seizures, hyperextensibility of joints, lung hypoplasia, cardiac dextroversion, midface hypoplasia, flat nasal bridge, and duplicated renal collecting system observed in single families [
4].
The causative gene in KS has been identified as
COL18A1, which encodes for collagen type XVIII α-1 chain. It is ubiquitously expressed in vascular and epithelial basement membranes and has multiple functions in ocular and neurologic development including maintenance of the basement membrane, cell proliferation, and angiogenesis [
5].
Herein, we describe two siblings with KS associated with polymicrogyria, an anomaly sporadically associated with KS [
2,
6]. Polymicrogyria is a condition characterized by multiple small gyri leading to an abnormally thick cerebral cortex. It presents with variety of clinical symptoms dependent on the specific region of the brain that is affected, although seizures and developmental delay are commonly described. Our first case is also noteworthy as the patient presented with a RD at only 7-months-old, which to our knowledge is the second youngest age reported to date in a patient with KS [
7]. We then briefly describe potentially promising treatment options for KS.
Discussion and conclusions
In this paper, we report two siblings who presented with poor BCVA along with high myopia and anisometropia. Retinal examination and OCT demonstrated thinning of the RPE and an atrophic appearance, with a serous RD observed in one child although no leakage was seen on FA. ERG in both patients demonstrated significant depression of the cone and rod system. Whole genome and mitochondrial DNA sequencing eventually uncovered a mutation in homozygous mutation in the COL18A1 gene, diagnostic of KS. Notably, neither patient had the characteristic encephalocele and both had polymicrogyria demonstrated on MRI.
Our findings add to the literature supporting the spectrum of brain anomalies observed with KS, including polymicrogyria. Additionally, our cases are consistent with other reported cases of KS with polymicrogyria in which polymicrogyria did not occur with midline occipital defects [
2,
6]. Therefore, head imaging may be helpful in the diagnosis of KS and associated CNS abnormalities in patients with characteristic retinal findings but lacking an encephalocele. While the patient in Case 1 did experience delay in motor and social development, the patient in Case 2 experienced normal developmental milestones. To our knowledge, neither patient has any other neurologic abnormalities. In previously reported cases of KS with associated polymicrogyria, developmental delay was observed in most patients [
2,
6].
The onset of RD at seven months of age in Case 1 was earlier than what is typically reported, as RDs tend to occur at the end of the first decade of life or later in patients with KS. There was one reported case of RD in the setting of KS identified at one month of age [
7] and another case identified “before the age of one” [
8]. KS is typically associated with rhegmatogenous RD, consistent with the associated vitreoretinal degeneration, as opposed to the serous RD observed in our patient [
9]. There is at least one prior case describing a serous RD occurring in a child with KS [
10]. Unfortunately however, the majority of case reports on patients with early onset of RD do not comment on the subtype of RD. [
6‐
8,
11] The finding of a serous retinal detachment is of interest, as vitreoretinal degeneration would typically result in a rhegmatogenous RD. We find no basic science research to suggest a potential pathogenesis of serous RD development in patients with KS.
In the absence of obvious neurologic symptoms, the differential diagnosis of KS includes but is not limited to cone-rod dystrophy, Leber congenital amaurosis, retinitis pigmentosa, microcephaly lymphedema chorioretinal dysplasia syndrome, and Stickler syndrome. Khan et al. suggest that a triad of smooth iridies, ectopia lentis, and characteristic vitreoretinal degeneration is pathognomonic of KS based on an observation of eight children [
10]. Notably, these findings were demonstrated in patients with an already known diagnosis of KS. We argue that the clinical triad described by Khan et al. is challenging to utilize within the clinical setting with an unknown diagnosis, and genetic testing is often essential for diagnosis. However, once a molecular diagnosis is reached, the patient should be reassessed to address possible associated ocular conditions of KS including pigment dispersion syndrome, RD, lens subluxation and cataracts [
6]. In addition, it is important to emphasize that the genetic testing results need to be correctly interpreted and correlate with the clinical findings to avoid misleading diagnosis, as in our first patient his initial retinopathy panel revealed a mutation in the CNGB3 gene associated with achromatopsia. The lack of correlation of this condition with his clinical findings led to additional genetic testing with subsequent whole exome and mitochondrial DNA sequencing demonstrating a mutation in the
COL18A1.
Although we contemplated repairing the serous RD in our patient, the prognosis for KS patients is often poor as could lead to the need for multiple interventions. Moysidis et al. describes a child with KS who underwent repair of a RD at 24 months of age and was also prophylactically treated with scleral buckle implantation [
11]. Four years later, the patient is still doing well without evidence of recurrent RD, suggesting that this represents a potentially promising surgical prophylactic option. Given that these patients have high risk of RD during their life time, we offered to the parents treatment options of peripheral laser retinopexy with and without scleral buckle surgery vs cryopexy to the periphery. In Case 1, the parents elected for observation. They did however agree to have peripheral cryo-retinopexy OD only to prevent possible progression of the RD.
While treatment for KS is often supportive, recent advancements in our understanding of the pathophysiology of the disease come from studies in
Drosophila [
12]. Mutation of the
COL18A1 gene resulted in mitochondrial structural disorganization that caused a decrease in energy generation and enhanced reactive oxygen species (ROS) production. Interestingly, treating the mutants with the angiotensin II type 1 receptor antagonist losartan, a conventional hypertensive medication, has been shown to attenuate mitochondrial ROS production, improve mitochondrial morphology and restore function, suggesting a viable avenue for further investigation. Considerable research interest in the ocular renin-angiotensin system and its role in disease may help guide future treatment options for patients with KS [
13].
Further investigation is necessary to enhance our understanding of the pathophysiology of KS so that we may offer improved medical and surgical treatments for our patients.