De novo CHD7 variant in a CHARGE syndrome preterm infant initially diagnosed as idiopathic hypogonadotropic hypogonadism: a case report and literature review.

BACKGROUND

CHARGE syndrome (CS), a rare and complex autosomal dominant disorder characterized by ocular coloboma, cardiac defects, choanal atresia, growth retardation, genital abnormalities, and ear malformations, is caused primarily by variants in the chromodomain helicase DNA-binding protein 7 (CHD7) gene. The clinical manifestations of CS frequently overlap with those of idiopathic hypogonadotropic hypogonadism (IHH), complicating diagnosis and management. To date, only a few cases of preterm infants with CS have been reported. Here, we describe the clinical features and genetic findings of a very preterm male infant who was initially diagnosed with IHH but was ultimately confirmed to have CS, carrying a de novo heterozygous CHD7 variant, highlighting the diagnostic and management challenges associated with this condition.

CASE PRESENTATION: A preterm male infant, born at 28 + 2 weeks with a birth weight of 1.15 kg, presented with micropenis and right radial polydactyly. Initial suspicion of IHH arose due to micropenis, cryptorchidism, and low levels of testosterone, LH, and FSH. Despite normal cranial MRI findings, further investigations revealed hsPDA, aortic arch narrowing, renal pelvis separation, and EEG abnormalities. Comprehensive genetic analyses, including whole-exome sequencing (WES), Sanger sequencing, and a Mini-gene Assay, confirmed the presence of a pathogenic de novo splicing variant in the CHD7 gene [c.5405-7G > A (NM_017780.4)]. As dysmorphic features progressed, the diagnosis was revised from IHH to CHARGE syndrome. Despite surgical and supportive treatments, the infant developed CRE sepsis and passed away after the withdrawal of life support.

CONCLUSIONS

To our knowledge, this is the first reported case of CS with polydactyly in a very preterm infant at approximately 28 weeks gestation. Furthermore, we summarized the clinical and genetic findings of previously reported cases with overlapping CS and IHH phenotypes. This study expands the clinical phenotypes of CHD7-related disorders and provides new insights into early diagnosis, management, and future research on the relationship between CS and IHH.