Table 4. [Differential Diagnosis of Clinical Findings...]. - GeneReviews®

Clinical Finding	Distinguishing Features	Comment
Motor/sensory neuropathy	Often autosomal dominant	See Charcot-Marie-Tooth Hereditary Neuropathy Overview.
Congenital ichthyosis	Acanthosis may be observed in SPLIS.	Congenital ichthyosis is a feature of several genetic syndromes. Nonsyndromic ichthyosis (e.g., autosomal recessive congenital ichthyosis) can be considered if ichthyosis is the presenting finding; syndromic ichthyosis can be assoc w/Netherton syndrome, Sjögren-Larsson syndrome, & trichothiodystrophy
Nonimmune hydrops	Enlarged/hemorrhagic adrenals	Many genetic conditions are assoc w/fetal hydrops (e.g., chromosome anomalies, RASopathies, & lysosomal storage disorders). ¹
Primary adrenal insufficiency	Adrenal calcifications, hypothyroidism, cryptorchidism, & micropenis may be assoc w/primary adrenal insufficiency.	Many disorders affect the adrenal cortex → inadequate production of adrenal steroids & features incl vomiting, hypoglycemia, poor weight gain, & fatigue. Causes can include: disorders that affect steroid biosynthesis, cholesterol metabolism, mitochondrial function (see Mitochondrial Disorders Overview); those assoc w/various metabolic defects (e.g., peroxisomal disorders); adrenal dysgenesis; & resistance to adrenocorticotropic hormone. ²
Primary immunodeficiency / T-cell lymphopenia (CD4 & CD8) w/or w/o low B & NK cells	Persons w/SPLIS have lymphopenia w/↓ T cells & frequently low B & NK cells; however, T-cell function & vaccine responsiveness is generally retained in SPLIS (vs in persons w/SCID).	Isolated T-cell deficiency may be found in many primary immune deficiencies (e.g., SCID, 22q11.2 deletion syndrome, CHARGE syndrome, FOXN1 haploinsufficiency, CD3 deficiency, & IL7R deficiency). ³ Combined T-, B-, & NK-cell deficiency can be seen in primary immune deficiencies incl adenosine deaminase deficiency & PNP deficiency.
Steroid-resistant nephrotic syndrome (SRNS)	High incidence of collapsing variant FSGS in SRNS ⁴	>50 monogenic causes of SRNS have been identified ⁵; disease is largely limited to kidneys in many affected persons.

Clinical Finding

Distinguishing Features

Comment

Motor/sensory neuropathy

Often autosomal dominant

See Charcot-Marie-Tooth Hereditary Neuropathy Overview.

Congenital ichthyosis

Acanthosis may be observed in SPLIS.

Congenital ichthyosis is a feature of several genetic syndromes.
Nonsyndromic ichthyosis (e.g., autosomal recessive congenital ichthyosis) can be considered if ichthyosis is the presenting finding; syndromic ichthyosis can be assoc w/Netherton syndrome, Sjögren-Larsson syndrome, & trichothiodystrophy

Nonimmune hydrops

Enlarged/hemorrhagic adrenals

Many genetic conditions are assoc w/fetal hydrops (e.g., chromosome anomalies, RASopathies, & lysosomal storage disorders). ¹

Primary adrenal insufficiency

Adrenal calcifications, hypothyroidism, cryptorchidism, & micropenis may be assoc w/primary adrenal insufficiency.

Many disorders affect the adrenal cortex → inadequate production of adrenal steroids & features incl vomiting, hypoglycemia, poor weight gain, & fatigue.
Causes can include: disorders that affect steroid biosynthesis, cholesterol metabolism, mitochondrial function (see Mitochondrial Disorders Overview); those assoc w/various metabolic defects (e.g., peroxisomal disorders); adrenal dysgenesis; & resistance to adrenocorticotropic hormone. ²

Primary immunodeficiency /
T-cell lymphopenia (CD4 & CD8) w/or w/o low B & NK cells

Persons w/SPLIS have lymphopenia w/↓ T cells & frequently low B & NK cells; however, T-cell function & vaccine responsiveness is generally retained in SPLIS (vs in persons w/SCID).

Isolated T-cell deficiency may be found in many primary immune deficiencies (e.g., SCID, 22q11.2 deletion syndrome, CHARGE syndrome, FOXN1 haploinsufficiency, CD3 deficiency, & IL7R deficiency). ³
Combined T-, B-, & NK-cell deficiency can be seen in primary immune deficiencies incl adenosine deaminase deficiency & PNP deficiency.

Steroid-resistant nephrotic syndrome (SRNS)

High incidence of collapsing variant FSGS in SRNS ⁴

>50 monogenic causes of SRNS have been identified ⁵; disease is largely limited to kidneys in many affected persons.

From: Sphingosine Phosphate Lyase Insufficiency Syndrome

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