Alport syndrome with bilateral simultaneous anterior and posterior lenticonus with severe temporal macular thinning

Abstract

Alport syndrome (AS) is a hereditary disease with various modes of inheritance, X-linked being the the most common. Anterior lenticonus is the characteristic abnormality along with perimacular and peripheral fleck retinopathy. Our two cases of AS had simultaneous anterior and posterior lenticonus with severe temporal macular thinning on optical coherence tomography with no specific renal symptomatology and were diagnosed as AS without any invasive renal biopsy. First patient was a 19-year-old man who presented with compound myopia due to bilateral anterior and posterior lenticonus with perimacular fleck retinopathy and lozenge sign and bilateral moderate sensorineural hearing loss (SNHL). Second patient was a 24-year-old man who presented with difficulty in vision due to bilateral anterior and posterior lenticonus with bilateral severe SNHL. Our cases emphasise the crucial role of an ophthalmologist in diagnosing AS before the onset of renal symptoms and prompting further nephrological work-up in the patient or the carrier.

Background

Alport syndrome (AS) is an inherited renal disease characterised by sensorineural hearing loss (SNHL), progressive renal failure and ocular abnormalities with X-linked, autosomal recessive and rarely autosomal dominant inheritance patterns caused by pathogenic variants in COL4A5, COL4A3 and COL4A4 genes. All the types of inheritance patterns are associated with a reduction in the corresponding collagen IV α chain and in the other chains of the heterotrimer α3α4α5 and basement membrane network.^{1 2} The characteristic ophthalmic manifestations described in the literature are dot and fleck retinopathy with an associated lozenge sign, anterior lenticonus and less frequently posterior polymorphous corneal dystrophy, posterior lenticonus, macular hole and temporal retinal thinning.^3–5 The prevalence of posterior lenticonus has been found in only 1–4 of 1 00 000 children.^{6 7} Temporal macular thinning has been described in multiple studies with variable incidence, ranging from 80%–90% men and 50%–75% women with X-linked Alport syndrome (XLAS).^{2 8 9}

Chen et al ⁹ have reported this temporal thinning as a relatively specific sign not only for the diagnosis, but also for prognostication of XLAS. They have also reported temporal retinal thinning being associated with a younger age of onset of renal failure.

We hereby describe two cases of young men with AS with rare presentation of bilateral simultaneous anterior and posterior lenticonus and severe temporal macular thinning without any renal symptomatology.

Case presentation

Case 1

A 19-year-old man presented with progressive diminution of vision and difficulty in hearing for the past 5 years. There were no renal complaints. There was history of a sibling having succumbed to renal failure due to some chronic kidney disease. He had best corrected visual acuity (BCVA) of 6/18 in the right eye and 6/12 in the left eye. Slit lamp biomicroscopy revealed bilateral anterior and posterior lenticonus (figure 1). Retinal examination revealed perimacular dot and fleck retinopathy with lozenge sign in both eyes (figure 2). Posterior segment spectral domain optical coherence tomography (SDOCT) showed bilateral temporal macular thinning (255 μm in the right eye and 252 μm in the left eye) and foveal thinning (201 μm in right eye and 210 μm in left eye) (figure 3). No corneal abnormality was found on evaluation.

Figure 1.

Case 1: Bio-microscopic slit lamp photographs—optical section showing anterior lenticonus (yellow arrow) and posterior lenticonus (white arrow): (A) right eye, (B) left eye. Bio-microscopic slit lamp photographs—retro-illumination showing oil droplet reflex of anterior and posterior lenticonus (blue arrow): (C) right eye, (D) left eye.

Figure 2.

Case 1: Fundus photograph showing lozenge sign or dull macular reflex with perimacular flecks (white arrow): (A) right eye and (B) left eye.

Figure 3.

Case 1: OCT macula showing temporal thinning (N, nasal; T, temporal): (A) right eye and (B) left eye. Thickness map showing temporal macular thickness: (C) right eye—255 μm and (D) left eye—252 μm.

Based on his clinical findings, the patient was assessed further; audiometric evaluation revealed bilateral moderate SNHL. Urinary examination of the patient showed proteinuria (100 mg/dL) with microscopic haematuria (red blood cells (RBCs) 10–15/high power field (HPF)) and a reduced 24 hours urinary volume (900 mL) with increased total urinary proteins (3060 mg/24 hours). There was mild derangement of renal function tests with blood urea raised to 50 mg/dL, serum creatinine to 2.24 mg/dL and serum uric acid to 7.34 mg/dL. Liver function tests were also deranged with albumin/globulin ratio being 0.9 and total serum proteins being 6.26 g/dL. Ultrasonography of kidney, ureter and bladder (KUB) revealed a normal right kidney but an irregular outline of the left kidney with nephrolithiasis and sediments in the bladder.

Patient was started on angiotensin converting enzyme (ACE) inhibitors for delaying the onset of end stage renal disease (ESRD). The decision for lens surgery was deferred for the time being.

Case 2

A 24-year-old man presented with complaints of progressive diminution of vision in both eyes for the past 9 years along with difficulty in hearing with no other systemic complaints. His BCVA was 6/9 in both eyes. Anterior segment examination revealed bilateral anterior and posterior lenticonus with posterior subcapsular cataract in the left eye (figure 4). Fundus examination showed decreased foveal reflex in both eyes (figure 5) and posterior segment SDOCT showed bilateral temporal macular thinning (right eye—237 μm and left eye—231 μm) (figure 6). Patient was satisfied with his vision with spectacle correction.

Figure 4.

Case 2: Bio-microscopic slit lamp photographs—optical section showing anterior lenticonus (yellow arrow) and posterior lenticonus (white arrow): (A) right eye, (B) left eye. Bio-microscopic slit lamp photographs—retro-illumination showing oil droplet reflex of anterior and posterior lenticonus (blue arrow): (C) right eye, (D) left eye.

Figure 5.

Case 2: Fundus photograph showing lozenge sign or dull macular reflex (white arrow): (A) right eye and (B) left eye.

Figure 6.

Case 2: OCT macula showing temporal macular thinning (N, nasal; T, temporal): (A) right eye, (B) left eye. Thickness map showing temporal macular thickness: (C) right eye—237 μm, (D) left eye—231 μm.

His otological evaluation revealed severe SNHL on pure tone audiometry. With a clinical diagnosis of AS, he was investigated for renal involvement. Investigations revealed massive proteinuria (3380 mg protein/24 hours) but no microscopic haematuria, raised blood urea (62 mg/dL) and raised serum creatinine (2.5 mg/dL). Ultrasonography KUB was unremarkable.

The patient did not have any family history of similar illness. There were no male siblings, and the mother was asymptomatic. However, mother’s urine examination revealed microscopic haematuria.

In view of massive proteinuria and deranged renal functions, patient was started on ACE inhibitors to delay end stage kidney disease.

Differential diagnosis

Cause of bilateral anterior lenticonus in most cases (>90%) is AS as reported in literature while AS, Down syndrome and Lowe’s syndrome are reported systemic associations of bilateral posterior lenticonus.^{10 11} In AS, posterior lenticonus is seen in 1–4 in 10 000 patients.⁶

In Lowe’s syndrome, a rare X-linked recessive disease, there is dysfunction in kidney and nervous system with low-molecular-weight proteinuria, renal tubular acidosis, hypercalciuria and aminoaciduria resulting in renal failure. Nearly all these patients are afflicted with congenital cataracts along with glaucoma in 50% of patients and other associated features like nystagmus, corneal keloids and amblyopia, which cause impairment of vision in early childhood.¹²

Bilateral anterior lenticonus is hence virtually pathognomic of AS, wherein it is absent at birth and usually occurs in second to third decade of life.¹³

Maculopathy is another manifestation of AS which has not been reported in Lowe’s syndrome.¹² The fleck-like lesions as seen in AS may also be seen in the retina in a number of inherited disorders, as white or yellow discrete dots throughout the fundus, most dense in mid-periphery without macular involvement. However, most of these inherited disorders are not associated with systemic disease and generally have autosomal recessive inheritance.¹⁴

Differentials for patients with asymptomatic proteinuria and haematuria include hereditary nephritis (AS), thin basement membrane nephropathy (TBMN) and IgA nephropathy (IgAN). TBMN and early stages of AS are clinically and ultra-structurally indistinguishable from each other. However, AS is much less common than TBMN and most patients demonstrate X-linked inheritance. Affected individuals of TBMN usually present with microscopic haematuria, sometimes proteinuria and hypertension but usually a normal renal function. On the other hand, most of the affected men with AS present with haematuria and end up in renal failure by the age of 20 years.¹⁵ Therefore, it is extremely important to differentiate these two disorders, with TBMN having a relatively benign course¹⁶ while AS having an inevitable progression to ESRD and the ability of treatment to slow the rate of deterioration of kidney disease in AS.¹⁷ Another differentiating feature between TBMN and AS is that in X-linked and autosomal recessive AS, expression of type IV collagen 3–5 chains is usually significantly reduced or absent whereas in TBMN, the expressions are comparable to normal levels.¹⁶

Ocular involvement described in TBMN is in the form of corneal dystrophy or pigmentation, arcus, cataracts, retinal pigment epithelium (RPE) clumping and maculopathy. However, the characteristic dot and fleck retinopathy and anterior lenticonus described in AS do not occur in TBMN. The RPE clumping described in TBMN is easily distinguishable from dot and fleck retinopathy of AS by its smaller size and more regular outline.¹⁵

IgAN, another differential for our patients, is characterised by episodic haematuria, proteinuria, hypertension and renal impairment, hallmark being macroscopic haematuria that usually occurs with or immediately after upper airway tract infection. However, ocular involvement in IgAN is infrequent, the most common association being uveitis. The characteristic anterior and posterior lenticonus as seen in AS have not been described in IgAN.¹⁸

Differentials of inherited renal disease with deafness include almost 80 disorders based on Mendelian inheritance pattern. The most common cause of inherited deafness associated with renal disease is AS. Other diseases one should be aware of are Epstein syndrome and Fechtner syndrome, Brachio-oto-renal syndrome and Familial hypo/hyperparathyroidism and deafness and renal disease.¹⁹ However, as opposed to AS most of these disorders have lens involvement in the form of cataract without any lenticonus while retinal involvement includes coloboma, RPE clumping, hamartoma, vascular abnormalities and crystals²⁰ but the dot and fleck retinopathy is rare in conditions other than AS.

Hence the findings of simultaneous anterior and posterior lenticonus with characteristic lozenge sign of maculopathy and temporal retinal thinning as in our cases along with sensorineural deafness and advanced chronic kidney disease with positive family history point to diagnosis of AS.

Treatment

Both the patients were started on ACE inhibitors to delay the onset of renal failure.

In case 1, the decision for cataract surgery was deferred for the time being and the patient was asked to review regularly. In case 2, the patient was satisfied with his refractive correction and hence refused surgery. He was also advised regular follow-up.

Outcome and follow-up

The first patient, on 1 year follow-up, was maintaining his BCVA and there was no evidence of deterioration of renal functions. The second patient has also not shown any progression of his anterior lenticonus or any worsening of his renal functions till the last follow-up.

Discussion

The diagnosis of AS is highly likely if there is glomerular haematuria and family history of AS with no other cause for haematuria, or if bilateral high tone SNHL, lenticonus, or fleck retinopathy are present or if the glomerular basement membrane lacks the collagen IV α5 chain. The current recommendation is that genetic testing should be performed to confirm the diagnosis of AS and to identify the mode of inheritance to help predict the risk of early onset renal failure.¹⁷ Genetic testing using Sanger sequencing had a reduced sensitivity and was time-consuming but now it has been replaced by next generation sequencing which has a very high sensitivity (>95%) and a reduced cost, however, it is still not widely available and economically viable for our patients.^{21 22} Hence, in individuals in whom diagnosis is unclear and genetic analysis is not available, it may be useful to examine the young patient’s mother or an older affected male relative.¹⁷

Typical ocular associations in patients of AS are dot and fleck retinopathy, and anterior lenticonus. Anterior lenticonus is often seen in early middle age, usually after the onset of renal failure and is highly suggestive of the diagnosis of AS. In XLAS, it is associated with early onset renal failure.³ Colville et al ²³ described the dull macular reflex or the ‘lozenge’ reflecting a severe perimacular dot and fleck retinopathy in patients with both XLAS and autosomal recessive disease, and found its importance, not only for the diagnosis but also for prognostication. They found the presence of lozenge sign as being associated with early onset renal failure.

Recently, there have been several reports of temporal retinal thinning as demonstrated by SDOCT in AS.^{3 9} Temporal retinal thinning has been recognised as a sensitive and a relatively specific marker for the diagnosis of XLAS in men with renal failure.¹ Savige et al ² evaluated a case series of AS for macular changes where they found that the mean thickness of retina in patients of AS was reduced in four of the nine macular regions, namely superior, temporal and inferior inner macula, and temporal outer macula. This can be seen even in mild disease without a clinically obvious retinopathy, as in our second patient. The authors commented that thinning was statistically significant at the foveal and temporal region of the macula, as found in both our cases.

The occurrence of anterior and posterior lenticonus in the same eye has been rarely reported in AS.^{24 25} In our cases both anterior and posterior lenticonus were present before ESRD. Presence of simultaneous anterior and posterior lenticonus combined with SDOCT segmentation analysis of temporal macular thinning can help in early diagnosis of AS and can predict the presence of renal pathology even in the absence of renal symptomatology.

This can thus serve as a biomarker of severe kidney disease and help in early diagnosis and timely treatment to delay the onset of ESRD.²⁴ It may preclude the need for performing renal biopsies especially in suspected XLAS patients and may also obviate the need for genetic testing. This has also been mentioned by Hanson et al ²⁶ who in their analysis of large cohort of patients referred with suspected X-linked AS confirmed that mutation detection frequency is highest when three or more diagnostic criteria are met,^{26 27} as in our cases where three criteria were met.

AS presenting with visual symptoms before the onset of renal failure and renal complaints is very uncommon. Presence of lenticonus and central retinopathy in AS usually indicate renal failure before the age of 30 years.2 4 5 28 Hence, presence of lenticonus and retinal changes can be useful in predicting early onset renal failure. Treatment with ACE inhibitors in AS before the onset of proteinuria, especially in individuals with genetic mutations or positive family history consistent with early onset renal failure, may delay the onset of ESRD and improve the life expectancy in these patients.^{17 29 30}

Our cases of AS highlight the importance of a complete ophthalmic evaluation of anterior and posterior segment with SDOCT segmentation analysis of temporal retinal thinning in male patients presenting with anterior lenticonus to predict early onset renal failure. The SDOCT analysis may also help in predicting the inheritance pattern particularly XLAS since this thinning is more severe in men with XLAS (reflecting the severity of the basement membrane changes).

Learning points.

• Early recognition of Alport syndrome (AS) is important because of its inevitable progression to end stage renal failure.

• Timely treatment can slow the rate of deterioration and improve life expectancy.

• Ophthalmological manifestations can help in predicting inheritance pattern with prognostication of renal disease in AS, without a renal biopsy.

• Retinal temporal thinning is diagnostic of X-linked Alport syndrome in men and is also associated with a worse basement membrane abnormality.

• The lozenge sign is also useful diagnostically and for prognostication since it is associated with early onset renal failure.