Knowledge on rare diseases and orphan drugs

The prevalence is unknown. Data from large pediatric registries suggest that it accounts for ~1% of steroid resistant nephrotic syndrome.

The main clinical features are spondyloepiphyseal dysplasia, growth retardation both pre- and post-natal, defective cellular immunity and episodic lymphopenia with increased susceptibility to life-threatening infections, and a progressive steroid-resistant nephrotic syndrome that leads to end-stage renal failure. Almost all patients have T-cell deficiency with a normal CD4/CD8 ratio. Hyperpigmented macules, thin hair and dysmorphic facial features (a triangular-shaped face, microdontia, broad depressed nasal bridge, narrow nasal ridge and a broad nasal tip) are common. Neurologic manifestations include atherosclerosis and cerebrovascular disease, which manifest as migraine-like headaches, cerebral ischemia, cardiac dysfunction and cognitive deficiency. Additional features may include hypothyroidism, enteropathy, normocytic or microcytic anemia and thrombocytopenia.

The disorder is caused by biallelic pathogenic variants in the SMARCAL1 gene (2q35) which encodes the chromatin remodeling protein, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1.

Diagnosis is based on careful clinical, biochemical and radiologic evaluation typically demonstrating osteopenia, ovoid and flattened vertebral bodies, and hypoplastic femoral heads and acetabular roofs. Some patients with progressive proteinuria might be diagnosed incidentally through multigenic mutational screening (next generation sequencing/whole exome sequencing).

Cartilage-hair hypoplasia is the main differential diagnosis.

Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.

The pattern of inheritance is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing variants) informing them that there is a 25% risk of having an affected child at each pregnancy.

Therapy is largely limited to the prophylaxis and management of the various disease manifestations, such as dialysis and renal transplantation, supplementation of hematopoietic growth factors for neutropenia, orthopedic surgery as required, preventive antiviral therapies and vaccinations, anticoagulation, immunosuppressive therapy for those with autoimmune manifestations, and thyroid hormone supplementation.

Life expectancy is limited to childhood or early adolescence in most patients, due to stroke, infections, bone marrow failure, and renal failure. Survival into adulthood has been reported for patients with milder late-onset forms of the disease and successful management of the renal manifestations.

Last update: April 2021 - Expert reviewer(s): Pr Beata LIPSKA-ZIETKIEWICZ | ERKNet*

* European Reference Network