Sphingosine-1-Phosphate Lyase Deficiency associated with Adrenal Insufficiency and Nephrotic Syndrome: two siblings with the same mutation and different clinical course

Rodrigo Martín; Moreno María Rosa; González Verónica Gabriela; Spizzirri Ana Paula; Balbi Viviana Alicia; Analía Morín

Introduction: Sphingosine-1-phosphate lyase 1 (SGPL1) deficiency is a recently discovered syndrome that associates primary adrenal insufficiency, hypothyroidism, nephrotic syndrome and neurological disease. We report two siblings with this condition and different clinical course.

Case 1: A 5-year-old boy with a history of three episodes of gastroenteritis with dehydration was evaluated (Table 1). Glucocorticoid adrenal deficiency and hypothyroidism were diagnosed during second year of life. One year after diagnosis he presented ichthyosis and neurological signs included paralysis of the third right cranial nerve and seizures. Brain MRI showed ischemic injuries areas. At 3 years of age he developed progressive proteinuria followed by kidney failure requiring dialysis. A kidney biopsy showed collapsing glomerulopathy. At 4 years of age he showed paralysis of the third left cranial nerve, flaccid paralysis of the right upper limb. At the same time mineralocorticoid adrenal deficiency was diagnosed. Genetic testing was performed showing three mutations in SGPL1 and one mutation in COL4A3 (Table 2).

Case 2: The older sibling, a 7-year-old boy with a generalized tonic clonic seizure at 2 years of age presented with skin hyperpigmentation on the face, elbows and hands. Diagnosis of glucocorticoid, mineralocorticoid deficiency and hypothyroidism was made (Table 1). Studies to assess short stature were normal, including arginine stimulation test to rule out growth hormone deficiency. During follow-up he showed nephrotic range proteinuria with normal glomerular filtration rate. Genetic testing revealed the same mutations in SGPL1 but not the COL4A3 mutation (Table 2).

Table 1. Initial laboratory findings
Laboratory results	CASE 1	CASE 2
ACTH (pg/ml)	245	1450
Cortisol (ug/dl)	12.1	1.6
Sodium (mEq/l)	128	130
Glycemia (mg/dl)	89	23
TSH (UI/ml)	14.55	11.5
Free T4 (ng/dl)	0.72	0.9
Qualitative Proteinuria	Positive	Negative

Table 2. Molecular biology findings
Molecular biology	Autosomal recessive variants (category 3 o VUS), in heterozygosity: First variant: NM-003901.4:c.44A>G-p. (Tyr15Cys) Second variant: NM-003901.4:c.1057A>G-p. (Lys353Glu) Third variant: NM-003901.4:c.1226T>G-p. (Met409Arg) Variant in COL4A3 gene, autosomal dominant, in heterozygosity:NM-000091.5:c.364G>T-p. (Val122Leu)	Autosomal recessive variants (category 3 o VUS), in heterozygosity: First variant: NM-003901.4:c.44A>G-p. (Tyr15Cys) Second variant: NM-003901.4:c.1057A>G-p. (Lys353Glu) Third variant: NM-003901.4:c.1226T>G-p. (Met409Arg)

Conclusion: Mutations in SGLP1 show variable clinical manifestations. These patients described above share the same mutations with different clinical courses. The presence of COL4A3 mutation may contribute to the differences in patient 1 regarding the severity of renal course. Studies should be carried out to understand this heterogenic condition to allow its earlier recognition.

IMPE Abstracts

P108