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

Abstract

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.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12887-025-06251-x.

Introduction

CHARGE syndrome (CS) is a complex autosomal dominant disorder that disrupts the development of craniofacial structures, cranial nerves, and multiple organ systems [1]. It is estimated that CS occurs in approximately 1 in 15,000 to 17,000 births and significantly impacts survival and long-term quality of life, with a high mortality rate—approximately 30% of affected children do not survive beyond the age of five [1, 2]. CS is characterized by a distinct constellation of clinical manifestations, including ocular coloboma (80–85%), congenital heart defects (60%), choanal atresia (60–65%), growth and/or development retardation (80%), genital and/or urinary anomalies (70–75% in males), and ear anomalies (including deafness and vestibular disorders) (80%) [3]. These manifestations underscore the multisystem nature of the disorder, posing significant challenges in its diagnosis and management.

Notably, CS is characterized by nonrandom associations of clinical features and has a diverse clinical presentation, which can lead to a wide range of congenital defects [4]. Typically, CS is diagnosed during the neonatal period, primarily due to airway obstruction caused by posterior nasal atresia or stenosis, a hallmark feature of the syndrome. Other critical clinical phenotypes include ocular abnormalities, external ear malformations, and hearing loss, all of which are pivotal for early diagnostic considerations [2]. Despite these distinctive features, distinguishing CS from other genetic conditions, such as Kabuki syndrome, 22q11.2 deletion syndrome can be challenging because of overlapping phenotypic traits [1]. Such overlaps can lead to misdiagnosis or a missed diagnosis, highlighting the importance of thorough clinical evaluation and genetic testing to ensure accurate differentiation of CS from phenotypically similar syndromes.

An additional key aspect of CS is its strong association with idiopathic hypogonadotropic hypogonadism (IHH), which occurs in 60–80% of CS patients. IHH is further classified into normosmic IHH (nIHH) and Kallmann syndrome (KS) depending on the presence or absence of olfactory dysfunction [5, 6]. Molecularly, the chromodomain helicase DNA-binding protein 7 (CDH7) gene is located on chromosome 8 (region 8q12), spans 188 kb, contains 38 exons and encodes a chromodomain helicase DNA-binding protein essential for chromatin remodeling and gene regulation [1, 7]. The CHD7 gene was the first pathogenic gene associated with CS to be identified and remains the most extensively studied gene. It is also the causative gene shared between CS and IHH. Thus, the triple correlation among the CHD7 gene, CS and IHH has emerged as increasingly significant [8]. The closer the overlapping clinical characteristics and genetic commonalities between IHH and CS are, the greater the likelihood that IHH may be either an important complication of CS or allelic disorder with CS [6, 9]. Given these complexities, delayed or incorrect diagnosis - especially problematic in the neonatal period - can potentially hinder early interventions, which is vital for optimizing outcomes.

Few studies have focused on neonates with CS who also exhibit IHH, particularly those born very preterm (< 32 weeks gestation). Additionally, CS patients with polydactyly are often misdiagnosed. Here, we present a case of a very preterm male infant with a de novo CHD7 variant, displaying marked abnormalities of the genitalia (micropenis) and limbs (polydactyly). This uncommon case expands the known genetic and clinical spectrum of CS and enhances neonatologists’ understanding of its association with IHH and its diverse manifestations.

Case presentation

A very preterm male infant was delivered at 28 weeks and 2 days of gestation, with a birth weight of 1.15 kg and Apgar scores of 6, 8, and 9 at 1, 5, and 10 min, respectively. He required prolonged mechanical ventilation due to complications related to prematurity. On admission to the neonatal intensive care unit (NICU) of the West China Second Hospital of Sichuan University, the infant presented with notable congenital anomalies. A micropenis (penis length less than 1.5 cm, approximately 1.3 cm) was identified (Fig. 1A), significantly below the expected range for neonates of comparable gestational age [10]. No abnormalities were found on palpation of the corpora cavernosa. Additionally, right radial polydactyly was observed through physical examination and orthopantomograms of the hand (Fig. 1B, C).

Fig. 1.

Clinical characteristic photos of the patient. Clinical characteristic photos.(A) Micropenis and cryptorchidism. (B-C) Right hand with radial polydactyly. (D-E) The dysmorphic ears with absence of the earlobe and the lower helical fold, and a triangular concha. (F) Square face with broad forehead, broad interocular distance, broad nasal root, collapsed nasal bridge and short neck

During hospitalization, the patient underwent an extensive set of hematological and biochemical tests. Sex hormone tests revealed subnormal levels of testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) (Table S1). On the basis of these clinical characteristics and laboratory data, the infant was initially suspected to have IHH. To further confirm this diagnosis, cranial magnetic resonance imaging (MRI) was performed, which revealed no apparent abnormalities in the hypothalamic-pituitary region. We subsequently performed a series of comprehensive diagnostic evaluations. An electroencephalogram revealed convulsive wave activity. Chest radiography demonstrated findings consistent with neonatal respiratory distress syndrome (NRDS) and an enlarged cardiac silhouette (Supplementary Figure A). Echocardiography identified a patent ductus arteriosus (PDA) measuring 2.7 mm in diameter and a slightly narrow descending aortic arch measuring 3 mm, both of which are confirmed by computed tomography angiography (CTA) (Supplementary Figure B-E); An electrocardiogram revealed sinus tachycardia, and suspected abnormalities of both the atria and left ventricular hypertrophy. Urinary ultrasound revealed partial separation of the left renal pelvis (2 mm) (Supplementary Figure F). Bedside funduscopy and otolaryngologic endoscopy revealed no significant abnormalities. The patient’s karyotype was normal male (46, XY) and the results of a newborn screening test and tandem mass spectrometry were normal. In light of the clinical presentation and diagnostic findings, a preliminary diagnosis of IHH was established for this infant (Table S2) [10].

Because multiple congenital malformations are generally not associated with IHH, we performed family-based whole-exome sequencing (WES) on this family to investigate the genetic etiology (Fig. 2A). WES successfully identified a de novo heterozygous splicing variant [c.5405-7G >A (NM_017780.4)], which has been previously reported in the literature, and is a popular variant site for research on the CHD7 gene (OMIM: 608892; chr8-:60850486), a known disease-causing gene for both IHH and CS [11–13]. Then, we chose to utilize Sanger sequencing to validate this candidate variant, precisely confirming the CHD7 variant site (Fig. 2B). The variant was classified as “Likely Pathogenic” (LP) according to the American College of Medical Genetics and Genomics (ACMG) guidelines [14],. Thus, to further evaluate the functional impact of the variant, a Mini-gene Assay was conducted to assess the c.5405-7G >A variant in CHD7 on splicing in vitro. The reverse transcription polymerase chain reaction (RT-PCR) was performed via RNA from blood leukocytes of the proband and his family [used as the wildtype (WT)] to amplify a fragment of CHD7 mRNA, and the products displayed a measurable increase in the molecular weight of variant-CHD7 [679 base pairs (bp)] compared with the normal fragment (674 bp) using electrophoresis (Fig. 2C). Subsequent analysis of the amplified cDNA showed an abnormal integration of 5 bp bases of intron 25 (CACAG) in the c.5405-7G >A variant clone, resulting in a frameshift and introduction of a premature termination codon (p.Gly1802Alafs*30) compared with the WT sequence (Fig. 2D, E). All sequences of primers used in this study are presented in Table S3.

Fig. 2.

Identification of a pathogenic splicing variant of CDH7 in the family. Identification of a pathogenic splicing variant of CDH7 in the family.(A) Pedigrees of the identified variant (c.5405-7G > A). The proband is indicated by black arrows. (B) Sequence chromatogram confirmed the presence of heterozygous CHD7 variant only in the proband. (C) RT-PCR analysis was performed on cDNA samples from the wildtype (lane 2) and the proband (lane 3). Lane 1 represents a DNA ladder, lane 4 includes the vector and lane 5 includes a blank control. (D) The pattern diagram showed the harmful effects caused by the CHD7 splicing variant in intron25. (E) Sanger sequencing revealed an abnormal integration of 5 bp bases of intron 25 in the amplified cDNA fragment of the proband

As the preterm infant grew, additional facial features consistent with CS became increasingly evident, including external ear malformations (bilateral dysplastic ears, absent earlobes, and triangular concha) (Fig.1D, E) and craniofacial abnormalities (square face with a broad forehead, hypertelorism, broad nasal root, collapsed nasal bridge and a short neck) (Fig. 1F). Ultimately, the patient was revised to be diagnosed with CS according to the most recent diagnostic criteria proposed by Hale et al. [4] (Table S4), which integrate the criteria of Blake et al. [15], Verloes et al. [16] and Bergmann et al. [17].

After the neonate’s diagnosis was confirmed, management focused on symptomatic treatment for complications, such as feeding intolerance, gastroesophageal reflux, hemodynamically significant patent ductus arteriosus (hsPDA), and edema. Supportive interventions, including blood transfusions, dobutamine, furosemide, and albumin, help temporarily stabilize the infant’s condition. The hsPDA failed to close with ibuprofen and acetaminophen. At 35 days after birth, the infant underwent surgical interventions consisting of patent ductus arteriosus (PDA) ligation and lateral thoracotomy for aortic coarctation repair; postoperative evaluation revealed persistent patent ductus arteriosus (PFO) and mild pericardial effusion. At two months, the patient developed a high fever, and blood cultures confirmed carbapenem-resistant Enterobacteriaceae (CRE) sepsis, which was controlled through aggressive antibiotic therapy. Initially, the patient was treated with cefoperazone-sulbactam, and ampicillin. Subsequently, due to changes in the patient’s condition, polymyxin B nebulizer was administered. Finally, the antibiotic regimen was adjusted to include linezolid, along with cefoperazone-sulbactam. Despite comprehensive medical interventions, the infant’s prognosis remained poor. After detailed discussions involving the hospital’s perinatal palliative care team, who provided counseling regarding prognosis, facilitated family decision-making, and ensured comfort care, the family chose to withdraw life-sustaining treatment. The infant died shortly thereafter.

Discussion

We present a unique and complex case of a very preterm infant initially diagnosed with IHH initially, but ultimately confirmed to have CS through the identification of multiple congenital anomalies, clinical examinations and genetic testing. Prominently, this case confirms the similarity of the phenotypic features of IHH and CS, combined with the masking effect of prematurity on classic CS features, significantly complicating the diagnostic process. This finding also highlights that IHH is more likely to serve as a specific phenotype for CS. This is in line with the hypothesis of Balasubramanian et al. [9].

Accurate early diagnosis of CS in very preterm infants is inherently challenging. While craniofacial anomalies are key diagnostic markers, the immature facial structures of preterm infants can obscure subtle dysmorphic features, such as underdeveloped external ears, leading to underrecognition of CS. In this patient, the initial presentation of micropenis and minor-features consistent with IHH-misguided the diagnostic focus toward IHH. However, the subsequent emergence of additional dysmorphic features, alongside genetic testing, redirected the diagnosis to CS. This case underscores the diagnostic ambiguity posed by prematurity and emphasizes the importance of being vigilant for CS in addition to considering IHH in premature infants with genital malformations.

Our patient presented with reproductive anomalies, including micropenis and sex hormone abnormalities, which fulfilled the diagnostic criteria for IHH. Available evidence suggests that reproductive anomalies in IHH stem from gonadotropin-releasing hormone (GnRH) deficiency, at least in part, CHD7 variants. This is because the CHD7 gene may have an impact on neuroendocrine developmental pathways in GnRH neurons in addition to neurodevelopmental effects [5, 18, 19]. Therefore, any newborn presenting with reproductive abnormalities, such as micropenis and cryptorchidism should first be evaluated for IHH thorough hormonal testing and via cranial MRI to assess anterior hypothalamic–pituitary function. In our case, the presence of polydactyly—an extremely rare limb anomaly in IHH—coupled with progressively emerging facial features not typically associated with IHH, prompted us to reconsider the diagnosis. Subsequent molecular genetic analyses, including whole-exome sequencing (WES), identified a suspected pathogenic CHD7 variant. This variant was further confirmed as a splicing mutation through Sanger sequencing and a Mini-gene Assay, ultimately shifting the clinical diagnosis toward CS.

To date, seven patients were initially diagnosed with IHH and subsequently confirmed as CS. The shared pathogenic gene variants underlying IHH and CS are thought to account for their overlapping phenotypes (Table 1). This reasoning was reinforced by the fact that CHD7 variants have been implicated as the primary genetic cause in more than 90% of CS cases and approximately 10% of IHH cases [1, 6, 17]. In general, patients with CS tend to have nonsense, frameshift and other null variants, whereas IHH patients tend to have missense variants of the CHD7 gene [18]. Previous studies have demonstrated that a large number of CHD7 variants and different types of CHD7 variants can result in diverse clinical manifestations. As hypothesized by Jongmans et al. [12] and Bergman et al. [17], there is an absence of correlation between genotype and phenotype in patients with CS. This finding is analogous to the conclusion we found in the present study. As more CHD7 variants are discovered, studying their effects on GnRH neuron development may reveal the molecular mechanisms behind the phenotypic differences between IHH and CS.

Table 1.

Review of 7 patients initially diagnosed with idiopathic hypogonadotropic hypogonadism but ultimately confirmed to have CHARGE syndrome

Patient Number	P1[6]	P2[6]	P3[6]	P4[20]	P5[8]	P6[21]		P7
GA	NA	NA	NA	NA	NA	38 W		28 + 2 W
Age of diagnosis	NA	NA	NA	15Y	19Y	3Y		18D
CHD7 variant	c.7282 C > T, (p.Arg2428Ter)	c.4234T > G (p.Tyr1412Asp)	c.2966G > A (p.Cys989Tyr)	c.5210 + 3 A > G	c.115 C > T, (p.Gln39Ter)	c.7027 C > T		c.5405-7G > A (p.Gly1802AlafsTer30)
Other variants	—	—	—	—	SMCHD1 c.2582T > C	—		—
CHARGE syndrome features	Coloboma, Abnormal ears, Brain deformities, Cardiovascular deformities	Choanal atresia/ Cleft lip/palate, Abnormal ears, Brain deformities	Coloboma, Abnormal ears, Cranial nerve abnormalities, Brain deformities	Coloboma, Choanal atresia/ Cleft lip/palate, Abnormal ears, Cardiovascular deformities, CS-related face, Genital deformities, Skeletal/limb deformities, Developmental delay/ Intellectual disability	Abnormal ears, Cranial nerve abnormalities, Genital deformities, Developmental delay/ Intellectual disability		Coloboma, Abnormal ears, Brain deformities, Cardiovascular deformities, Feeding difficulties/ Tracheoesphageal Fistula, Genital deformities, Developmental delay/ Intellectual disability	Abnormal ears, Brain deformities, Cardiovascular deformities, Feeding difficulties, Tracheoesphageal Fistula, CS-related face, Genital deformities, Skeletal/limb deformities Renal deformities
Other phenotypes	Nasal cartilage distortion	Oval palate	Atropy of optic chiasma	High arched palate	—	—		—
Initial diagnosis	KS	KS	KS	nIHH	KS	KS		IHH
Final diagnosis	CS	CS	CS	CS	CS	CS		CS
ACMG criteria	P	LP	LP	P	P	NA		LP
Surgery	NA	Bilateral Posterior Nostril Atresia Repair Surgery	NA	NA	Cochlear implantation	NA		PDA ligation and thoracic aortic constriction

§ P7 is our patient; According to diagnostic criteria by Hale. CHARGE syndrome (CS): 2 majors + any number of minor criteria.

§ Abbreviations: CS: CHARGE syndrome; KS: Kallmann syndrome; nIHH: normosmic Idiopathic hypogonadotropic hypogonadism; −: negative symptoms; NA: Not available.

CS is a typically sporadic condition characterized by extensive genetic and phenotypic variability, often involving multiple organ systems (e.g., cardiac, auditory, and endocrine) [4]. Genetic variations can be categorized into distinct types, exhibiting both distinctive characteristics and shared traits. For example, genetic similarity and clinical heterogeneity between CS and IHH are shown in these seven cases of CHD7 variants in Table 1 (c.7282 C >T, c.4234T >G, c.2966G >A, c.5210 + 3 A >G, c.115 C >T, c.5405-7G >A, etc.) [6, 8, 20, 21]. Table S5 presents a comparison of the clinical features between CHARGE syndrome and IHH. However, no genotype-phenotype associations were found, despite the fact that IHH is a shared phenotype. Currently, this clinical heterogeneity has led to the absence of standardized treatment protocols for CS. Instead, a highly individualized, multidisciplinary approach involving neonatology, endocrinology, cardiology, otolaryngology, and medical genetics is needed. In our patient, supportive therapies, surgical correction of a hemodynamically significant patent ductus arteriosus, and targeted interventions for respiratory failure and infection led to temporary clinical improvement. However, the severity of systemic involvement poses significant therapeutic challenges, highlighting the need for comprehensive, collaborative care to address the multifaceted nature of CS.

Conclusions

This case illustrates the diagnostic and management complexities of CS in a very preterm neonate. Clinically, prematurity can obscure classic CS features, whereas phenotypic overlap with IHH further complicates early diagnosis. Concurrently, the presence of polydactyly in this patient serves to increase the specificity of the clinical presentation of CS patients and this finding thereby strengthens the correlation between polydactyly and the diagnosis of CS, particularly during the early neonatal period. Additionally, the identification of a de novo CHD7 splicing variant emphasizes the utility of advanced molecular diagnostics in guiding clinical decision-making. Further studies of preterm infants with pathogenic CHD7 variants are warranted to explore potential links between prematurity, CHD7 dysfunction, and the phenotypic spectrum of CS. Ultimately, establishing a multidisciplinary, evidence-based framework is essential to optimize outcomes in these medically fragile patients.

Abbreviations

ACMG

American college of medical genetics and genomics

CHD7

Chromodomain helicase DNA-binding protein 7

CRE

Carbapenem-resistant enterobacteriaceae

CS

CHARGE syndrome

CTA

Computed tomography angiography

FSH

Follicle stimulating hormone

GnRH

Follicle stimulating hormone

IHH

Idiopathic hypogonadotropic hypogonadism

KS

Kallmann syndrome

LH

Luteinizing hormone

MRI

Magnetic resonance imaging

NICU

Neonatal intensive care unit

nIHH

Normosmic idiopathic hypogonadotropic hypogonadism

NRDS

Neonatal respiratory distress syndrome

PFO

Patent foramen ovale

RT-PCR

Real-time polymerase chain reaction

WES

Whole-exome sequencing

Authors’ contributions

Jiaxi Wu: Data curation, methodology, validation, completing the original draft. Zhuo Huang: Genetic technology guidance, revision and review of articles.Yi Yang, Binlu Zhu, and Rong Zou: Clinical data collection, article revision.Yu Tan, Wencong Yao: Operators of genetic tests, genetic data collection.Tao Xiong: Funding acquisition, methodology, resources, project administration, and manuscript revision.

Funding

This work was supported by National Natural Science Foundation of China (82371723), the Science and Technology Bureau of Sichuan Province (2024YFFK0273), Health Commission of Sichuan Province Medical Science and Technology Program (24CGZH13), the National Key R&D Program of China (2021YFC2701700, 2021YFC2701704), Innovative Research Project from 0 to 1 of Sichuan University (2023SCUH0021).

Data availability

The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2025) in National Genomics Data Center (Nucleic Acids Res 2025), China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA011302) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.

Declarations

Ethics approval and consent to participate

This study was strictly conducted in accordance with the Declaration of Helsinki and approved by the Ethical Review Board of West China Second University Hospital, Sichuan University (YXKY 2024435). Signed and informed consent was obtained from the parents of the patient.

Consent for publication

Signed and informed consent for publication of the details of their medical case and any accompanying images was obtained from the patient’s parents.

Competing interests

The authors declare no competing interests.