Reni Syndrome

Editor In Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Alara E. Dagsali

Overview

• RENI syndrome (RENI) is a genetic condition characterized by steroid-resistant nephrotic syndrome (SRNS) (NPHS14, OMIM 617575) and a range of multisystemic manifestations. RENI syndrome (RENI) results from an autosomal recessive homozygous or compound heterozygous mutation in the SGPL1 gene located on chromosome 10q21.

• Affected individuals typically manifest in infancy or early childhood, showcasing progressive renal dysfunction linked to focal segmental glomerulosclerosis (FSGS), leading to end-stage renal disease (ESRD) within a few years. Alternatively, some infants exhibit primary adrenal insufficiency. In utero presentations may involve fetal hydrops and fetal demise. Additional disorder features encompass ichthyosis, acanthosis, adrenal insufficiency, immunodeficiency, and neurologic defects. Isolated primary adrenal insufficiency is observed in rare cases.

Historical Perspective

• The autosomal recessive inheritance association was first reported by Prasad et. al and Lovric et. al in 2017. In 2017, Prasad et al. identified 4 different variants of SGPL1 in five families with loss-of-function mutations in the SGLP-1 gene are causing primary adrenal insufficiency, steroid-resistant nephrotic syndrome (SRNS), primary hypothyroidism, neurological symptoms, and cryptorchidism. In the same year, Lovric et al. found that autosomal recessive mutations in SGPL1 also can cause facultative ichthyosis, adrenal insufficiency, neurologic involvement, and immunodeficiency. They identified 9 different recessive variants of SGPL1 in seven families with SRNS. Renal biopsies also showed focal segmental glomerulosclerosis (FSGS) and diffuse mesangial sclerosis (DMS)

Pathophysiology

• RENI syndrome is a rare genetic disorder caused by mutations in the SGPL1 gene. These mutations result in the loss of a protein that regulates a signaling molecule in the body. As a result, patients with RENI syndrome experience problems in their kidneys, adrenal glands, and skin. The mutations disrupt the balance of certain lipid molecules, affecting the immune system and various body tissues. Multiple studies have provided evidence linking SGPL1 gene mutations to this disorder.

Causes

• Researchers identified mutations in the SGPL1 gene in multiple patients with RENI syndrome. These mutations are responsible for the disorder and are often homozygous or compound heterozygous, meaning that the affected individuals inherit two mutated copies of the gene.
• The mutations in the SGPL1 gene lead to a loss of function of the SGPL1 protein and its enzyme activity. This protein plays a role in regulating the levels of a signaling molecule called S1P.
• SGPL1 deficiency affects various tissues in the body, including the adrenal glands, leading to adrenal insufficiency. It can also cause kidney problems and skin-related issues like ichthyosis.
• Changes in S1P metabolism due to SGPL1 mutations have systemic effects, including the accumulation of certain sphingolipid intermediates like ceramides.
• The mutations in SGPL1 can result in alterations in sphingolipid levels, which affect T-cell regress and play a crucial role in various tissues, especially the kidney.
• The types of SGPL1 mutations identified include frameshift, splice site, missense, and truncating mutations, all of which lead to reduced or absent SGPL1 protein and enzyme activity.
• Several studies discussed in the text confirm the association between SGPL1 mutations and RENI syndrome, with functional studies and genetic analyses.

Classification

• There is no established system for the classification of Reni Syndrome.

Epidemiology and Demographics

• Most affected patients present in infancy or early childhood.
• The youngest age of onset of disease was a day after birth, the oldest age is 19 years.

Differential Diagnosis

• In cases where children with central nervous system (CNS) and steroid-resistant nephrotic syndrome (SRNS) exhibit extra-renal manifestations, especially adrenal insufficiency, immunodeficiency, developmental delay, and hypothyroidism, it is advisable to conduct genetic testing for SGPL1. This testing can help rule out nephrotic syndrome caused by specific SGPL1 variants.
• Distinguishing between genetic and idiopathic forms of SRNS through genetic panel testing is crucial. These two forms of SRNS entail entirely different treatment regimens and prognosis.

Risk Factors

• There are no risk factors associated with the development of Reni syndrome.

Screening

• Early detection of this disease can expedite the identification of linked co-morbidities, potentially decreasing the progression of chronic kidney disease (CKD) and minimizing long-term complications associated with endocrinopathy. Published literature indicates a bleak prognosis, with nearly 50% mortality in reported cases (15 out of 35, plus 4 cases of fetal demise), predominantly within the first year of life.

Diagnosis

Diagnostic Study of Choice

• Considering the reports of isolated adrenal or renal disease during presentation, it is relevant to include SGPL1 in diagnostic genetic panels for primary adrenal insufficiency (PAI) and steroid-resistant nephrotic syndrome (SRNS), especially when observed in combination.
• Due to the multi-systemic and progressive characteristics of this form of primary adrenal insufficiency (PAI) and nephrotic syndrome, obtaining a genetic diagnosis is crucial. This is essential for ensuring optimal management and conducting appropriate screening for comorbidities in these patients.

History and Symptoms

• The high population of the patients progressed to end-stage renal disease or died in infancy or early childhood.
• The patients show SRNS syndromic features with additional symptoms.
• Some of the extra-renal features are:
  • SRNS
  • Fetal Hydrops
  • Primary Adrenal Insufficiency
  • Ichthyosis
  • Other endocrine or gonadal defects
  • Neurologic Deficits
    • Microcephaly
    • Cranial Nerve Defects
    • Peripheral Neuropathy
  • Severe Immunodeficiency
  • Lymphopenia
  • Multiple Bacterial Infections
  • Failure to thrive
  • Prior Fetal loss

Physical Examination

• Clinical examination is essential for identifying potential extra-renal manifestations associated with syndromic genetic steroid-resistant nephrotic syndrome (SRNS). These manifestations may include different combinations of primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, ichthyosis, neurologic involvement (such as developmental delay, seizures, and ataxia), immunodeficiency, and skeletal abnormalities.

Electrocardiogram

• There are no specific ECG findings associated with Reni syndrome. However, additional diagnostic check-ups may be required to investigate related extra-renal manifestations.

X-ray

• There are no specific x-ray findings associated with Reni syndrome. However, additional diagnostic check-ups may be required to investigate related extra-renal manifestations.

Echocardiography or Ultrasound

• There are no specific echocardiography and ultrasound findings associated with Reni syndrome. However, additional diagnostic check-ups may be required to investigate related extra-renal manifestations.

CT scan

• There are no specific CT scan findings associated with Reni syndrome. However, additional diagnostic check-ups may be required to investigate related extra-renal manifestations.

MRI

• There are no specific MRI findings associated with Reni syndrome. However, additional diagnostic check-ups may be required to investigate related extra-renal manifestations.

Other Imaging Findings

• There are no other imaging findings that may be used to diagnose Reni syndrome.

Other Diagnostic Studies

• There are no other diagnostic studies that may be used to diagnose Reni syndrome.

Treatment

• While future research may unveil targeted genetic therapies, heightened awareness of the syndrome can facilitate earlier recognition, leading to quicker diagnosis, timely intervention, and informed genetic counseling for affected families.
• Genetic SRNS is not treated with glucocorticoids and immunosuppressants rather than idiopathic SRNS.
• SRNS is the most common acquired cause of ESRD requiring transplantation in children.