Rhegmatogenous retinal detachment in an adolescent with Kniest Dysplasia: A case report

Abstract

Purpose

To report a rare case of adolescent high myopia with rhegmatogenous retinal detachment (RRD) caused by Kniest Dysplasia.

Observations

A 17-year-old boy with high myopia presented with 4-day progressive vision loss in his left eye. Ophthalmic examination revealed lattice degeneration in the right eye and RRD involving the macula in the left eye. Systemic evaluation revealed brachydactyly, restrictive ventilatory impairment, and spinal/pelvic anomalies. Whole exome sequencing identified a de novo heterozygous COL2A1 variant, confirming the diagnosis of Kniest Dysplasia, a severe type II collagenopathy. The right eye received prophylactic laser photocoagulation, while the left eye underwent scleral buckling.

Conclusions and importance

This study highlights the importance of ocular evaluation in the comprehensive management of systemic connective tissue diseases.

Highlights

• •Diverse collagenopathies require gene-specific sequencing for differential diagnosis.
• •Children with high myopia should be screened for systemic diseases.
• •Patients with connective tissue disorders should be evaluated for eye diseases.

1. Introduction

Kniest Dysplasia is a rare autosomal dominant disorder caused by COL2A1 mutations, disrupting type II collagen synthesis. To date, ophthalmic complications associated with Kniest Dysplasia have been documented in only a handful of articles, which predominantly involve non-Asian populations.¹ Kniest Dysplasia manifests with skeletal dysplasia, ocular abnormalities, and hearing loss. Skeletal abnormalities in patients with Kniest Dysplasia are often noticed by the patients or their parents, whereas eye anomalies may not be detected until visual impairment occurs. Ocular features include high myopia, vitreoretinal degeneration, and retinal detachment. Early intervention is critical to prevent irreversible vision loss. We present a Han Chinese ancestry case of skeletal abnormalities with rhegmatogenous retinal detachment (RRD) and high myopia, highlighting the necessity of systemic examination for this disease leads to its diagnosis.

2. Case report

A 17-year-old male patient, who was 139 cm tall and weighed 75 kg, was admitted to our ophthalmology ward from the clinic after presenting with an acute, painless decline in vision in his left eye for 4 days. The patient had high myopia with a refractive error of −12.0 D in both eyes. His best corrected visual acuity (BCVA) was 20/30 in the right eye and 20/1000 in the left eye. A comprehensive family history assessment was conducted, and his parents reported no family history of ocular or skeletal disorders.

Upon physical examination, in addition to his short stature (Fig. 1A), brachydactyly (short fingers) was also observed (Fig. 1B), which might be associated with underlying genetic or developmental factors. A detailed ophthalmic evaluation was then performed. The right eye showed lattice degeneration without retinal detachment (Fig. 2A). The left eye was diagnosed with RRD accompanied by proliferative vitreoretinopathy that had extended into the macula region (Fig. 2B). Overall, the retina of his left eye did not show significant contraction. There was a combined acute and chronic retinal detachment that involved all quadrants except the nasal and superonasal retina. Chronic detachment was observed in the superotemporal and inferotemporal periphery, accompanied by predominantly subretinal proliferative membranes, as shown in Fig. 2, the superficial retinal vessels were not obscured by the proliferative tissue, which is indicative of a subretinal rather than an epiretinal position. Atrophic retinal holes with non-rolled, non-tractional edges were identified in the inferotemporal region (marked with an asterisk in Fig. 2B), which also exhibited the most extensive subretinal proliferation.

Fig. 1.

Clinical photographs of the patient's short stature and fingers. A 17-year-old male patient presented with high myopia and short stature, along with painless vision loss in his left eye for 4 days. (A) The patient measured 139 cm in height (standard deviation score < −5, <0.1 percentile) and (B) showed disproportionately short fingers in relation to the palm.

Fig. 2.

Wide-field fundus photography of both eyes in a 17-year-old male presenting with high myopia and short stature with painless vision loss at his left eye for 4 days. (A) Lattice degeneration in the peripheral retina of the right eye (arrow).(B) Retinal detachment in the left eye, showing retinal holes (asterisk), proliferative vitreoretinopathy (arrows).

To comprehensively assess the patient's condition, additional examinations were conducted. Computed tomography of the head, spine, pelvis and limbs revealed spinal scoliosis with vertebral flattening and multiple endplate irregularities (Fig. 3). Bilateral hip joints showed horizontal acetabula with degenerative changes and asymmetric joint space narrowing in a narrowed pelvic cavity (Fig. 3B). Pulmonary function test indicated moderate restrictive ventilatory impairment. Left eye ultrasound biomicroscopy (UBM) demonstrated the lens and suspensory ligaments were intact. Neither bilateral hearing abnormalities nor heart abnormalities were detected in the pure tone tympanogram and echocardiography, respectively. Whole exome sequencing (WES) of the patient and his parents revealed that the patient had a de novo heterozygous COL2A1 variant (c.4121A > G, p.Q1374R), which was verified by Sanger sequencing (Fig. 4). The WES performed by Beijing Giantmed Medical Diagnostic Lab (The laboratory holds medical practice licensure issued by the People's Republic of China, including the specialized field of cellular and molecular genetics.) revealed a heterozygous COL2A1 missense variant (c.4121A > G, p.Gln1374Arg). This variant was determined to be de novo (PS2) and was absent from population databases (ESP database, 1000 Genomes Project, ExAC_ALL, ExAC_EAS, gnomAD_genome_ALL, and gnomAD_genome_EAS) (PM2). In silico predictions supported a deleterious effect (Revel, SIFT, Polyphen-2, Mutation Taster and GERP++ predicted as Deleterious, Damaging, Probably_damaging, Disease_causing and Conserved, respectively) (PP3), and the patient's phenotype was highly specific for a COL2A1-related disorder (PP4). Based on these findings and in accordance with ACMG-AMP guidelines,² the variant was classified as likely pathogenic.

Fig. 3.

Computed tomography of the spine and pelvis in a 17-year-old male presenting with high myopia and short stature with painless vision loss at his left eye for 4 days. (A) Vertebral flattening (arrows) and multiple endplate irregularities (arrowheads). (B) Spinal scoliosis (arrowhead), bilateral hip joints showed horizontal acetabula with degenerative changes and asymmetric joint space narrowing (arrows) in a narrowed pelvic cavity (asterisks).

Fig. 4.

Sanger sequencing identified a de novo heterozygous variant in COL2A1 (C.4121A > G, p.Q1374R) in a 17-year-old male patient presenting with high myopia and short stature with painless vision loss at his left eye for 4 days, but absent in both parents.

The diagnosis of Kniest dysplasia was confirmed by molecular genetic testing combined with the above pathological features, despite the absence of variant in his parents, the lack of typical orofacial abnormalities (e.g., midface hypoplasia, cleft palate), and normal auditory function. In the differential diagnosis of pediatric patients presenting with high myopia complicated by retinal detachment, a systematic approach to evaluate genetic syndromes is imperative. The clinical investigation should particularly include syndromes with collagenopathies and connective tissue disorders, including Stickler syndrome (types I and II), Wagner syndrome, Knobloch syndrome (COL18A1-related), homocystinuria, and Marfan syndrome.

Prophylactic barrier laser photocoagulation was applied to the lattice degeneration areas in his right eye, while an urgent scleral buckling (SB) procedure was performed on the left eye. Additionally, the patient was advised to undergo systemic management including polysomnography and an orthopedic clinic referral, but he declined.

At the six-month postoperative follow-up, BCVA in the right eye was stable at 20/30, while the left eye had improved to 20/400, although the retina remained partially detached. Further vitrectomy was recommended, but the patient declined. He was advised to undergo annual retinal screenings to monitor for disease progression or new retina hole formation.

3. Discussion

Kniest Dysplasia is classified as a type II collagenopathy. Type II collagen predominantly constitutes cartilage tissues, ocular vitreous body, retina, lens, and inner ear. The COL2A1 gene spans over 4000 base pairs and contains numerous mutation-prone loci. Different mutation sites may induce missense, nonsense, or frameshift variations. These genetic alterations result in diverse abnormalities in protein expression, including secondary and tertiary structural defects and impaired protein interactions, ultimately manifesting as clinical heterogeneity that ranges from mild skeletal dysplasia to perinatal lethality.³

In ophthalmic practice, Stickler syndrome types I and II (COL2A1-related and COL11A1-related, respectively) represent the most prevalent collagenopathies with ocular-articular manifestations, occurring in approximately 1:7500 to 9000 live births. While diagnostic and therapeutic protocols for Stickler syndrome are well-established,⁴ Kniest Dysplasia demonstrates additional severe phenotypic features including extreme short stature with finger shortening, obvious spinal dysplasia, and metaphyseal enlargement of long bones.^3,5 Since its initial description by Dr. Kniest in 1952,⁶ fewer than 150 cases of Kniest Dysplasia have been reported worldwide,¹ with even fewer reports involving Asian populations.^1,7, 8, 9, 10, 11 Although not all patients with Kniest Dysplasia develop high myopia,¹² some early case reports of Kniest Dysplasia did not include descriptions of the eyes, especially the fundus examination.^1,13 This may reflect a historical lack of awareness regarding the need for ophthalmic evaluation in these patients rather than the true absence of ocular involvement.

The patient in this case initially presented with short stature during his childhood, though previous evaluations at local institutions failed to establish a definitive diagnosis. The investigations at the local clinic likely focused on common etiologies such as growth hormone deficiency, nutritional deficiencies, or constitutional growth delay, and they did not find any abnormalities. However, overlooking potential systemic or genetic disorders is a critical oversight, given that 80 % of children with a height standard deviation score < −3 (approximately ≤0.1 percentile) have underlying pathological causes necessitating immediate evaluation.¹⁴ This 17-year-old patient's height of 139 cm is markedly below the median height of 172 cm for Chinese males of the same age (3rd percentile: 161 cm, 0.1 percentile: 152.5 cm), indicating that the height of this patient is exceeded threshold for diagnostic workup.

During our evaluation, despite the absence of Marfanoid features and cardiac anomalies, the identification of rhizomelic limb shortening, brachydactyly, and an abnormal gait prompted WES. This revealed a heterozygous COL2A1 missense variant (c.4121A > G, p.Q1374R), a de novo variant with no familial segregation. This molecular confirmation underscores the diagnostic challenges in atypical presentations and highlights the necessity of genetic testing in severe short stature with syndromic features. The absence of family history in this de novo variant case further illustrates the unpredictable penetrance of COL2A1 variants. Cautions must be paid in clinical practice, even in sporadic presentations.^3,15

This case also emphasizes the necessity of performing detailed retinal examinations including peripheral fundus evaluation in patients with suspected connective tissue disorders, to detect subclinical vitreoretinal abnormalities. Additionally, for patients suspected of having a COL2A1 variant, a standardized framework for skeletal, auditory, cardiopulmonary, and craniofacial assessments is imperative, as it is suspected in type II collagenopathies.

RRD is rare in children, although it is often a complication seen in cases of children with high myopia, and is a sign of hereditary connective tissue disorders.¹⁵ In addition to Kniest dysplasia, these disorders include Stickler syndrome, Knobloch syndrome, Spondyloepiphyseal dysplasia congenita, Ehlers-Danlos syndrome, and others. This phenotypic overlap suggests the need for a comprehensive systemic evaluation and genetic testing in patients exhibiting disproportionate growth along with concurrent ocular or auditory abnormalities. In this particular patient, pulmonary function tests revealed moderate restrictive ventilatory impairment, which is consistent with the patient reporting he needs a seated sleeping position. Fortunately, UBM, echocardiography and audiometric assessments ruled out lens abnormality, heart defects and hearing loss in this patient, respectively.

For syndromic RRD in adolescents with high myopia, our therapeutic approach aligns with conventional pediatric RRD protocols. Given the strong vitreoretinal adhesion typically seen in younger patients, along with the fact that this patient's detached retina was not stiff and contracted, and that most proliferative membranes were located subretinally, primary SB without vitrectomy was selected as the preferred intervention, consistent with published recommendations.¹⁶ The patient's moderate restrictive ventilatory impairment further supported the choice of SB over vitrectomy, as we sought to reduce general anesthesia time in light of reported respiratory risks associated with Kniest Dysplasia.¹⁷ Although successful vitrectomies have been reported in Kniest Dysplasia patients,^7,10 we considered SB the most appropriate initial surgical approach. The procedure involved external drainage of subretinal fluid, cryotherapy, scleral encircling, and silicone tamponade, all of which were performed successfully. While surgical outcomes are known to correlate inversely with the degree of myopia, and efficacy declines in eyes exceeding −10 D,¹⁶ partial retinal reattachment was achieved. Postoperative BCVA improved from 20/1000 to 20/400. The persistence of shallow detachment, likely due to chronic subretinal fibrosis and vitreous traction, highlights the crucial need for early fundus examination to prevent irreversible structural damage. According to a study on postoperative outcomes in Stickler syndrome patients with retinal detachment, the majority of cases involved giant retinal tears and were managed primarily with SB combined with pars plana vitrectomy and silicone oil tamponade.¹⁸ Given that our patient presented with atrophic holes rather than a giant tear, we considered SB as the primary intervention, with vitrectomy reserved as a contingency procedure.

In the patient's fellow eye, peripheral retinal laser photocoagulation was applied to the lattice degeneration areas. This prophylactic strategy is similar to the Cambridge Stickler syndrome management protocol,^19,20 which aims to prevent retinal detachment. The Cambridge protocol has been shown to reduce the incidence of RRD by 6- to 8- fold in COL2A1-positive cohorts, despite the risk of transient complications. Although technical differences exist between laser photocoagulation and cryotherapy, laser photocoagulation allows for more precise treatment of retinal degeneration areas and minimizes collateral damage when guided by wide-field imaging.

4. Conclusions

Pediatricians and ophthalmologists should be careful for potential ocular complications in children with short stature or skeletal dysplasia, particularly those with high myopia. Similarly, children presenting with high myopia should undergo a comprehensive evaluation, including genetic testing and assessment of the respiratory, cardiovascular, and auditory systems, to rule out underlying systemic disorders.

CRediT authorship contribution statement

Xiao Hu: Writing – original draft, Methodology, Conceptualization. Peiwen Li: Writing – review & editing, Methodology, Conceptualization. Weiquan Liang: Writing – review & editing, Methodology, Conceptualization. Wenjing Peng: Writing – review & editing, Methodology, Conceptualization. Xiangbin Kong: Writing – review & editing, Supervision, Conceptualization.

Patient consent

Consent to publish this case report has been obtained from the patient in writing.

Authorship

All authors attest that they meet the current ICMJE criteria for Authorship.

Funding

This study received no funding or grant support.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.