Pediatric Summary Report

Secondary Findings in Pediatric Subjects

Non-diagnostic, excludes newborn screening & prenatal testing/screening

• Status (Pediatric): Passed (Consensus scoring is Complete)
• Curation Status (Pediatric): Released 1.0.0
• Status (Adult): Passed (Consensus scoring is Complete)
• GENE/GENE PANEL: COL4A5, COL4A3, COL4A4
• Condition: Alport syndrome
• Mode(s) of Inheritance: X-linked

Actionability Assertion

• COL4A5 ⇔ 0018965 (alport syndrome): Strong Actionability
• COL4A3 ⇔ 0018965 (alport syndrome): Strong Actionability
• COL4A4 ⇔ 0018965 (alport syndrome): Strong Actionability

Actionability Rationale

The expert consensus agreed with assertion computed according to the rubric. It should be noted that most evidence for this condition was from males with X-linked Alport syndrome, but still applicable to the dominant and recessive forms.

Final Consensus Scores

Gene Condition Pairs: COL4A5 ⇔ 0018965 (OMIM:301050) COL4A3 ⇔ 0018965 (OMIM:104200) COL4A3 ⇔ 0018965 (OMIM:203780) COL4A4 ⇔ 0018965 (OMIM:203780)

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of the Intervention	Total Score
Progression of renal disease / Referral to a specialist for evaluation to guide treatment with angiotensin-converting enzyme inhibitors (ACEi)	2	3C	2B	3	10CB
Functional impairments from loss of hearing and vision / Regular audiologic and ophthalmologic evaluations to optimize hearing and vision	2	2C	3B	3	10CB

1. What is the nature of the threat to health for an individual carrying a deleterious allele?

Prevalence of the Genetic Condition

The most widely used prevalence estimate of Alport syndrome (AS) is 1/5000, based on finding of about 300 individuals in Utah and southern Idaho in a population of 1,500,000 people. The incidence of AS was found to be 1/53,000 in Finland, and 1/17,000 in southern Sweden. [1, 2, 3]

Clinical Features

AS is a familial renal disorder with a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course. The hallmark of AS is microhematuria which can progress to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD). AS frequently has cochlear and ocular manifestations. Sensorineural hearing loss (SNHL) is progressive into adulthood. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), recurrent corneal erosion, and bilateral posterior subcapsular cataracts. Aneurysms of the thoracic and abdominal aorta have been described in a small number of males. Diffuse leiomyomatosis of the esophagus, tracheobronchial tree, and female reproductive tract has been reported in several dozen families and is associated with specific deletions. [1, 2, 4, 5, 6, 7, 8]

Natural History

There are three forms of AS:
•X-linked AS (XLAS) accounts for about 65-85% of individuals. In males, manifestations are typically more severe; in females, X chromosome inactivation in individual tissues contributes to variable clinical features. Males have persistent microhematuria from early in life. In all males, renal disease progresses to ESRD in the absence of treatment. In males, truncating variants in COL4A5 are associated with an earlier age at onset of kidney failure; risk of ESRD before age 30 is estimated as 90% for large rearrangements and pathogenic nonsense and frameshift variants, 70% for splice variants, and 50% for missense variants. In males, progressive SNHL is usually present by late childhood or early adolescence, and interior lenticous typically becomes apparent in late adolescence or early adulthood. In females, renal disease ranges from asymptomatic disease to lifelong microhematuria to renal failure at a young age. In females, progressive SNHL is typically later in life, lenticonus may not occur, and central retinopathy is rare.
•Autosomal recessive AS (ARAS) accounts for about 15% of individuals. Males and females are affected equally. Renal disease progresses to ESRD in the absence of treatment. Progressive SNHL is usually present by late childhood or early adolescence. Anterior lenticous typically becomes apparent in late adolescence or early adulthood.
•Autosomal dominant AS (ADAS) accounts for approximately 5-20% of AS individuals. ADAS is typically a slowly progressive disorder. ADAS can vary from an asymptomatic disease to more severe renal disease. Most have hematuria, although it may be intermittent, and proteinuria is frequent with advancing age. ESRD is frequently delayed until later adulthood. SNHL is relatively late in onset. Ocular involvement is rare. [1, 2, 3, 4, 5, 6, 7, 8]

2. How effective are interventions for preventing harm?

Patient Management

To establish the extent of disease and needs in an individual diagnosed with AS, the following evaluations are recommended:
•Renal: Baseline testing of urine protein excretion
•Hearing: Baseline audiogram
•Vision: Baseline ophthalmologic evaluation. (Tier 4) [1]

Affected individuals should be referred to an interested nephrologist for long-term management and have their risk factors for progressive renal failure optimized, including careful management of hypertension, proteinuria, and dyslipidemia. Children with Alport syndrome are typically normotensive, but hypertension frequently develops in adolescent and young adult patients. A blood pressure goal of about the 50th percentile in individuals with AS is recommended. (Tier 2) [4, 8]

Treatment with angiotensin-converting enzymes inhibitors (ACEi) may delay ESRD. Males with XLAS and all individuals with ARAS are recommended to be treated with ACEi at diagnosis (if older than 12-24 months), even before the onset of proteinuria. Guidelines differ slightly for the initiation of treatment in females with XLAS; one guideline recommends initiation of treatment at onset of microalbuminuria while a second recommends initiation at onset of microalbuminuria, hypertension, or renal impairment. Guidelines also differ for ADAS; one guideline does not provide recommendations for treatment in ADAS while another recommends initiation of treatment at onset of microalbuminuria. One study of children with AS (mean age 8.8 years; 98% males; 84% XLAS and 16% with autosomal) with isolated hematuria or hematuria and microalbuminuria included a randomized, placebo-controlled arm (n=20) and an open-label comparison arm (n=42; included 24 pretreated children and 18 children whose parents refused randomization) who were compared to a cohort of untreated children (n=28). The study found that ACEi therapy decreased the risk of disease progression by almost half (hazard ratio 0.51 (95% CI: 0.12-2.20)), though this was not statistically significant. In the randomized arm, only 27% (3 of 11) in the treatment group and 56% (5 of 9) in the placebo group progressed during follow-up. Of the open-arm group, 41% (17 of 42) progressed compared to 43% (12 of 28) of untreated patients. Adjusted for age and disease status at baseline, treatment again reduced progression by almost 50%, although the reduction was not significant. A retrospective analysis of registry data of 283 patients with genetically confirmed AS (91% male, 84% with XLAS) followed for over two decades suggests ACEi therapy delays the onset of ESRD once proteinuria has developed. Patients not treated with ACEi (n=109) started dialysis at a median age of 22 years while patients treated with ACEi at onset of impaired renal function (n=26) delayed dialysis to a median age of 25 and patients who received ACEi at onset of proteinuria (n=115) delayed dialysis to a median age of 40. Sibling pairs confirmed these results, showing earlier therapy in younger patients significantly delayed dialysis by 13 years compared to later or no therapy in older siblings. ACEi therapy significantly improved life expectancy beyond the median age of 55 years of the no-treatment cohort. A second study among 207 males with XLAS reported that males with ACEi treatment had onset of ESRD at a median age of >50 years while those who did not receive treatment had onset at median age of 28 years. Further, no treatment and treatment in males with truncating variants had onset at a median age of 16 and 28 years, respectively, while those with non-truncating variants had onset at a median age of 33 years and 50 years, respectively. (Tier 2) [4, 8]

Women with AS are at risk for pregnancy complications including increased proteinuria, renal insufficiency, worsened hypertension, and preeclampsia. The risks are higher in women with preexisting renal insufficiency, proteinuria, or hypertension. Optimal maternal and fetal outcomes may require the involvement of a nephrologist as well as high-risk obstetrics. (Tier 4) [1]

Surveillance

For males with XLAS, and children with ARAS, formal hearing evaluation should begin at age 5 to 6 years with annual follow-up examination. Evaluations can be delayed until the onset of proteinuria in females with XLAS. Hearing-loss due to AS usually responds well to amplification with hearing aids. Speech discrimination is typically well preserved. (Tier 2) [8]

Ophthalmologic exam for anterior lenticonus should begin at about age 15 years in males with XLAS who have truncating variants in COL4A5 and in males and females with ARAS. Subsequent examinations should be scheduled annually. Lenticonus worsens until visual symptoms require treatment, and most patients eventually require surgery. Treatment for both symptomatic lenticonus and cataract is lens removal and intraocular lens implantation. Lenticonus does not recur after lens replacement. (Tier 2) [8]

Recommended surveillance also includes:
•Regular follow-up by a nephrologist with urinalysis and renal function assessment is recommended every six to 12 months
•Blood pressure, repeated annually. (Tier 4) [1]

Circumstances to Avoid

Affected individuals should avoid ototoxic medication and industrial noise exposure to minimize further hearing loss. (Tier 2) [4, 8]

Carrier females should be strongly discouraged from kidney donation because of their own increased risk of renal impairment and hypertension. (Tier 2) [4]

Patients should avoid nephrotoxic drugs. (Tier 4) [3]

3. What is the chance that this threat will materialize?

Mode of Inheritance

X-linked
AS can be transmitted in an X-linked, autosomal recessive, and autosomal dominant manner. Rare digenic inheritance has been reported. [1, 2, 3, 4, 5, 6, 7, 9]

Prevalence of Genetic Variants

AS is due to pathogenic variants in COL4A5 (80-85% of individuals; all XLAS), COL4A3 (12-15% of individuals; ~45% are ARAS and ~55% are ADAS), and COL4A4 (5-8% of individuals; ~45% are ARAS and 55% are ADAS). Pathogenic variants are different in each family with XLAS, and more than 700 variants have been described. (Tier 3) [1, 4]

Penetrance

The penetrance of XLAS is 95%. (Tier 3) [4]

In males with XLAS, 90% develop ESRD by age 40 and SNHL develops in 80-90% by age 40. (Tier 3) [1, 8]

In males with XLAS, the frequency of other clinical manifestations has been estimated as:
•100% have microhematuria
•All develop proteinuria, hypertension, and renal insufficiency with advancing age
•30-40% develop ocular lesions
•13-30% develop anterior lenticonus
•50% develop central fleck retinopathy
•60% develop peripheral coalescing retinopathy
•14% develop maculopathy.
•30% develop perimacular flecks (Tier 4) [1, 4]

In females with XLAS, the frequency of clinical manifestations has been estimated as:
•Almost all (95%) have hematuria
•75% develop proteinuria
•40% develop ESRD by age 80 years
•30-40% have hearing loss
•40% have peripheral retinopathy
•30% develop perimacular flecks (Tier 3) [1, 4, 8]

In individuals with ARAS, the frequency of clinical manifestations has been estimated as :
•100% have microhematuria
•All develop proteinuria, hypertension, and renal insufficiency develop with advancing age
•15-20% develop anterior lenticonus.
•30% develop perimacular flecks (Tier 4) [1]

A retrospective analysis of 30 genetically diagnosed individuals with ARAS reported that 40% developed hearing loss, with 20% developing hearing loss by age 10. (Tier 3) [8]

In individuals with ADAS, 4-13% will have hearing loss. (Tier 3) [8]

Relative Risk

Information on relative risk was not available for the Pediatric context.

Expressivity

Information on variable expressivity was not available for the Pediatric context.

4. What is the Nature of the Intervention?

Nature of Intervention

Interventions identified in this report include regular surveillance for renal, vision, and hearing manifestations. ACEi are also recommended for some patients. Side effects from the use of ACEi are rare, non-severe, and include hyperkalemia, dry cough, symptomatic hypotension, fatigue, oral ulcers, polyuria and polydipsia, aggressive behavior and agitation, sleep disorder, fetopathy, and withdrawal because of ‘ineffectiveness.’ [8]

5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care?

Chance to Escape Clinical Detection

80% of females with XLAS are diagnosed only after their son or other male relative has presented, though they are at risk of developing renal failure later in life. (Tier 4) [4]

Date of Search: 11.04.2021

Reference List

1. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Mirzaa GM, Amemiya A. Alport Syndrome. GeneReviews®. (1993)

2. Alport syndrome. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=63

3. Hertz JM, Thomassen M, Storey H, Flinter F. Clinical utility gene card for: Alport syndrome. Eur J Hum Genet. (2012) 20(1476-5438).

4. Savige J, Gregory M, Gross O, Kashtan C, Ding J, Flinter F. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. (2013) 24(1533-3450):364-75.

5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. COLLAGEN, TYPE IV, ALPHA-3; COL4A3. MIM: 120070: 2022 Feb 09. World Wide Web URL: http://omim.org.

6. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ALPORT SYNDROME 2, AUTOSOMAL RECESSIVE; ATS2. MIM: 203780: 2019 Jan 31. World Wide Web URL: http://omim.org.

7. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ALPORT SYNDROME 3, AUTOSOMAL DOMINANT; ATS3. MIM: 104200: 2019 Feb 01. World Wide Web URL: http://omim.org.

8. Kashtan CE, Gross O. Clinical practice recommendations for the diagnosis and management of Alport syndrome in children, adolescents, and young adults-an update for 2020. Pediatr Nephrol. (2021) 36(1432-198X):711-719.

9. Gross O, Tönshoff B, Weber LT, Pape L, Latta K, Fehrenbach H, Lange-Sperandio B, Zappel H, Hoyer P, Staude H, König S, John U, Gellermann J, Hoppe B, Galiano M, Hoecker B, Ehren R, Lerch C, Kashtan CE, Harden M, Boeckhaus J, Friede T, German Pediatric Nephrology (GPN) Study Group and EARLY PRO-TECT Alport Investigators. A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome. Kidney Int. (2020) 97(1523-1755):1275-1286.