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Pierson syndrome: for professionals

Overview

IncidenceRare (less than 100 cases described in literature), incidence unknown
InheritanceAutosomal recessive
Genes involved (OMIM No.)LAMB2 (#150325)
SymptomsMicrocoria and abnormal iris structureUsually, nephrotic syndrome picked up on neonatal screen
Ocular FeaturesMicrocoriaAbnormal iris structureShallow anterior chamberGlaucomaCataractRetinal detachment
Systemic featuresCongenital nephrotic syndromeDelayed cognitive developmentMuscle weakness and hypotoniaRespiratory distress
Key investigationsOcular surface and fundus examinationGonioscopy and tonometryUltrasound biomicroscopyOptical coherence tomography Renal function testsRenal biopsy
Molecular diagnosisWhole genome sequencing (structural eye disease panel)
ManagementOcular Medical: mydriatics and topical IOP lowering dropsSurgical: pupil enlargement, cataract removal, and increasing aqueous outflow if required. Supportive: correcting refractive error Systemic Paediatric/clinical genetics reviewMultidisciplinary approach if systemic features are present
Therapies under ResearchDefining clinical characteristicsGenotype-phenotype correlation studiesMolecular mechanism studies

Clinical Phenotype

Presenting features

Pierson syndrome is a rare genetic disorder characterized by congenital nephrotic syndrome, ocular abnormalities, and neurodevelopmental impairment1,2.

Ocular

  • Bilateral microcoria: a hallmark ocular feature which aids in diagnosis during ocular examinations.
  • Other ocular features: can include cataract, glaucoma and retinal detachment3,4,5,6.

Systemic

  • Congenital nephrotic syndrome: infants affected by Pierson syndrome present shortly after birth with nephrotic syndrome, characterized by profound proteinuria, hypoalbuminaemia, oedema, and hyperlipidaemia7,8. The severe renal impairment leads to significant morbidity.
  • Neurodevelopmental impairment: some patients display neurodevelopmental challenges, including delayed motor skills and cognitive development9. These impairments can vary widely in severity.
  • Muscle weakness and hypotonia: present in some patients, this contributes to motor difficulties and overall physical limitations.
  • Respiratory distress: newborns may experience severe respiratory distress. Prompt medical intervention is essential to manage this potentially life-threatening symptom.

Genetics

Gene: LAMB2 (3q22.3)

OMOM no.: #150325

Inheritance pattern: autosomal recessive

Protein: laminin beta-2

Location: Glomerular basement membrane and RPE basement membrane

Function: Complete loss of function alleles result in more severe clinical disease, whereas missense mutations give rise to a milder phenotype10,11. The disruption impairs the structural integrity of the glomerular basement membrane, leading to increased permeability. Consequently, proteins that are essential for normal bodily functions, such as albumin, leak into the urine, causing proteinuria, hypoalbuminemia, and oedema—hallmark features of Pierson syndrome. Disruption in the structural integrity of the RPE can impair its functions, including supporting the photoreceptor cells and maintaining the blood-retinal barrier.

Key Investigations

Newborn screening programmes are the mainstay of diagnosing Pierson Syndrome. The condition should be suspected in babies with nephrotic syndrome and microcoria. Other specific key investigations are as follows:

Ocular

  1. Ocular examination: Hallmark feature of severe microcoria with variable response to cycloplegic agents. Patients can also display abnormal iris architecture and cataracts (usually posterior lenticonus)1,3.
  2. Oculomotor examination: presence of strabismus and nystagmus indicating ocular motor control issues.
  3. Fundoscopy: abnormalities in retinal structure, potentially including colobomas, retinal detachment (RD) and/or persistent foetal vasculature (PFV)12.
  4. Refractive error: patients often have high myopia.
  5. Gonioscopy and intraocular pressure: may find shallow or flat anterior chamber and increased IOP.
  6. Ultrasound B-scan: can find increased axial length, presence of colobomas, retinal detachment, and hypoplastic ciliary body.
  7. Optical coherence tomography (OCT): can identify potential retinal abnormalities.
  8. Genetic testing (LAMB2 gene sequencing): identification of pathogenic variants in the LAMB2 gene, confirming the diagnosis of Pierson syndrome.

Systemic

  • Renal function tests: nephrotic syndrome (profound proteinuria, hypoalbuminemia, oedema, and hyperlipidaemia)
  • Renal biopsy (light and electron microscopy): Diffuse mesangial matrix increase or FSGS lesions. Absent or markedly decreased GBM staining for laminin β2 chain. Irregular thick and thin zones on both sides of the lamina densa of the GBM with lamellation13.
  • MRI of the brain: abnormalities in brain structure may be present if neurological symptoms.

Diagnosis

A combination of clinical features, renal biopsy findings, and genetic testing is crucial for the accurate diagnosis of Pierson syndrome. Genetic testing, particularly sequencing of the LAMB2 gene, is confirmatory.

Differential diagnoses

Differential diagnoses include congenital nephrotic syndromes, Alport syndrome, and other genetic kidney diseases presenting with early-onset proteinuria. Clinical and genetic evaluations are necessary to differentiate these conditions from Pierson syndrome.

Management

Ocular

1) Glaucoma and Cataract

  • Refer to glaucoma specialist for further management and long-term follow-up.

2) Genetics

  • If the patient has not had genetic testing previously, refer to the ocular genetics service or clinical genetics locally for whole genome or LAMB2 sequencing if there is a high suspicion.

3) Supportive

  • Correcting any associated refractive errors
  • Close monitoring of vision with rapid initiation of amblyopia treatment if detected
  • Referral to low vision services (if indicated)
  • Directing patients and families to supporting organisations
  • Encourage the use of assistive technology that may improve quality of life

Systemic

1) Renal management:

  • Referral to nephrology services for regular monitoring of renal function through blood tests and urinalysis to assess renal health and identify signs of deterioration.

2) Multidisciplinary support (referral to appropriate services):

  • Nutritional support: ensuring adequate nutrition and maintaining a balanced diet to support overall health and growth, especially in paediatric patients.
  • Physical and occupational therapy: physical and occupational therapy sessions to improve motor skills, muscle strength, and overall functional abilities.
  • Speech therapy: speech therapy sessions if speech and communication difficulties are present.
  • Paediatric neurologist: prescribing antiepileptic medications to manage seizures if neurological symptoms are present. Medication choice and dosage are determined based on the type and frequency of seizures.

Family management and counselling

Pierson syndrome is inherited in an autosomal recessive manner. Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis.

Emotional and social support

Genetic counsellors (GCs) and Eye Clinic Liaison Officers (ECLO) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist service

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

Current research

Current research efforts are directed towards understanding the molecular mechanisms underlying Pierson syndrome and genotype-phenotype correlation studies16. Various case reports have been published in the literature which allows clinicians and researchers to gain a better understanding of the clinical manifestations of this syndrome and investigate other genes. There are no current clinical trials on gene therapy for this condition.

Related links

References

  1. Bredrup C, Matejas V, Barrow M, Bláhová K, Bockenhauer D, Fowler DJ, Gregson RM, Maruniak-Chudek I, Medeira A, Mendonça EL, Kagan M. Ophthalmological aspects of Pierson syndrome. American journal of ophthalmology. 2008 Oct 1;146(4):602-11.
  2. Pierson M, Cordier J, Hervouuet F, Rauber G. An unusual congenital and familial congenital malformative combination involving the eye and kidney. Journal de genetique humaine. 1963 Dec 1;12:184-213.
  3. Matejas V, Al-Gazali L, Amirlak I, Zenker M. A syndrome comprising childhood-onset glomerular kidney disease and ocular abnormalities with progressive loss of vision is caused by mutated LAMB2. Nephrology Dialysis Transplantation. 2006 Nov 1;21(11):3283-6.
  4. Amirlak I, Sabnis SG, Al-Gazali L, Abdulrazzaq YM. A syndrome of immune complex glomerulonephritis and ophthalmic abnormalities. Journal of medical genetics. 1999 Aug 1;36(8):641-4.
  5. Zenker M, Aigner T, Wendler O, Tralau T, Müntefering H, Fenski R, Pitz S, Schumacher V, Royer-Pokora B, Wühl E, Cochat P. Human laminin β2 deficiency causes congenital nephrosis with mesangial sclerosis and distinct eye abnormalities. Human molecular genetics. 2004 Nov 1;13(21):2625-32.
  6. Zurowska A, Załuska-Leśniewska I, Zenker M. LAMB2 gene mutation as a cause of congenital nephrotic syndrome with distinct eye abnormalities and hypotonia. Przeglad Lekarski. 2006 Jan 1;63:37-9.
  7. Świetliński J, Maruniak-Chudek I, Niemir ZI, Woźniak A, Wilińska M, Zacharzewska J. A case of atypical congenital nephrotic syndrome. Pediatric Nephrology. 2004 Mar;19:349-52.
  8. VanDeVoorde R, Witte D, Kogan J, Goebel J. Pierson syndrome: a novel cause of congenital nephrotic syndrome. Pediatrics. 2006 Aug 1;118(2):e501-5.
  9. Wühl E, Kogan J, Zurowska A, Matejas V, Vandevoorde RG, Aigner T, Wendler O, Lesniewska I, Bouvier R, Reis A, Weis J. Neurodevelopmental deficits in Pierson (microcoria‐congenital nephrosis) syndrome. American journal of medical genetics Part A. 2007 Feb 15;143(4):311-9.
  10. Hasselbacher K, Wiggins RC, Matejas V, Hinkes BG, Mucha B, Hoskins BE, Ozaltin F, Nürnberg G, Becker C, Hangan D, Pohl M. Recessive missense mutations in LAMB2 expand the clinical spectrum of LAMB2-associated disorders. Kidney international. 2006 Sep 2;70(6):1008-12.
  11. Minamikawa S, Miwa S, Inagaki T, Nishiyama K, Kaito H, Ninchoji T, Yamamura T, Nagano C, Sakakibara N, Ishimori S, Hara S. Molecular mechanisms determining severity in patients with Pierson syndrome. Journal of Human Genetics. 2020 Apr;65(4):355-62.
  12. Gooley K, Williams P, Mack H, Zhu V, Langsford D, Pianta T, Barit D, Mahmood K, Savige J. A comparison of the ocular features in Pierson and Alport syndrome: a case report and literature review. Ophthalmic Genetics. 2023 Sep 3;44(5):417-22.
  13. Lusco MA, Najafian B, Alpers CE, Fogo AB. AJKD atlas of renal pathology: Pierson syndrome. American Journal of Kidney Diseases. 2018 Apr 1;71(4):e3-4.
  14. Doucette LP, Footz T, Walter MA. FOXC1 regulates expression of prostaglandin receptors leading to an attenuated response to latanoprost. Investigative Ophthalmology & Visual Science. 2018 May 1;59(6):2548-54.
  15. Enyedi LB, Freedman SF. Safety and efficacy of brimonidine in children with glaucoma. Journal of American Association for Pediatric Ophthalmology and Strabismus. 2001 Oct 1;5(5):281-4.
  16. Suzuki R, Sakakibara N, Ichikawa Y, Kitakado H, Ueda C, Tanaka Y, Okada E, Kondo A, Ishiko S, Ishimori S, Yamamura T. Systematic Review of Clinical Characteristics and Genotype-Phenotype Correlation in LAMB2-Associated Disease. Kidney International Reports. 2023 Jul 4.
Updated on January 31, 2024
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