Recurrent small for gestational age and death in male infants as a potential warning sign of neglected incontinentia pigmenti: a case report

The IKBKG gene, located on Xq28, is responsible for the X-linked dominant disorder Incontinentia Pigmenti (IP). Hemizygous male fetuses carrying pathogenic IKBKG variants typically die in utero, while the few survivors often develop severe immunodeficiency and ectodermal dysplasia. We report a family in which recurrent low birth weight and post-neonatal deaths in two consecutive male offspring prompted a comprehensive family-based genetic evaluation, ultimately revealing previously unrecognized maternal IP and a familial pathogenic IKBKG variant. A 29-year-old woman had a history of two adverse reproductive outcomes. Both offspring (III-1 and III-2) exhibited a gradual decline in growth potential from the second trimester and were born small for gestational age (SGA), with birth weights below the 3rd and 10th percentiles for gestational age, respectively. they subsequently developed multisystem dysfunction and died at 45 and 32 days of age, respectively. The initial whole-exome sequencing (WES) of III-1 did not identify any pathogenic variants that could explain the clinical phenotype. After excluding common maternal factors such as hypertension, immune dysfunction, and infection, trio-based WES identified a frameshift variant in IKBKG (NM_001099857.5( IKBKG ):c.519-3_519dup) in both the mother (II-4) and her affected son (III-1). In conjunction with her history of generalized brown hyperpigmentation during infancy and residual pigmentation confined to the legs in adulthood, these findings led to a diagnosis of IP in II-4. Following the diagnosis, the couple underwent in vitro fertilization (IVF) with preimplantation genetic testing for monogenic disorders (PGT-M). A blastocyst shown by PGT-M to be free of the familial pathogenic IKBKG variant was transferred, resulting in the birth of a male infant. At 45 days of age, comprehensive physical examination demonstrated no abnormalities. We identified NM_001099857.5( IKBKG ):c.519-3_519dup as a pathogenic variant that may be associated with recurrent SGA and male infant death, highlighting the clinical manifestations in affected offspring during both the fetal and postnatal periods. SGA may represent an underrecognized phenotypic feature of pathogenic IKBKG variants. For couples experiencing recurrent unexplained severe SGA and loss of male offspring, this case highlights a potential etiological screening strategy involving the exclusion of common causes followed by evaluation for X-linked disorders.