Sifrim–Hitz-Weiss/CHD4-related syndrome: A new case report

To the editor:

A 5-month-old boy presented with micropenis and growth failure. He was born vaginally at 40⁺⁶ weeks to healthy and non-consanguineous parents. His birth weight was 3.3 kg and his length at birth was 50 cm (−0.33 SD). He had a brief history of asphyxia and neonatal jaundice after birth, which resolved with treatment. Subsequently, he gradually showed developmental delay. He could not hold his head steady until the age of 5 months and only started sitting independently at 9 months of age and walking independently at 1.5–2 years.

The child's height was 64 cm (−1 SD), and his weight was 7.9 kg (−1 SD) at his first visit at the age of 5 months. His reaction to sound was positive but slow. He showed hypomimia and hypotonia. The craniofacial manifestations included square face, prominent forehead, posterior hairline, arched eyebrows with the lateral third displaying sparseness, ptosis, widely spaced eyes, myopia, eversion of the lateral third of the lower eyelid, short nose with a flat nasal root, gothic arch, cupped ear, ape palmprint, and hypotonia. He had a small penis (2 cm × 1 cm) and a thick scrotum. His left testicle was palpable with a volume of 1–2 mL, while the right testicle was retracted in the groin but could be pushed into the scrotum. There was skeletal deformity of his feet, and he had delays in gross and fine motor skills in comparison with his peers. The paternal height was 172 cm, and the maternal height was 162 cm. Neither of the parents had dysmorphic facial features or abnormal physical signs. There was no family history of similar symptoms.

His laboratory results on presentation were insulin-like growth factor 1 (IGF-1) less than 25.0 ng/mL (reference range 55.0–327.0 ng/mL), insulin-like growth factor binding protein 3 (IGFBP-3) 1.6 μg/mL (reference range 0.7–3.6 μg/mL), and testosterone (post-human chorionic gonadotropin [hCG] stimulation) 0.333 ng/mL (reference range 0–0.107 ng/mL). The function of his liver and kidney and the hormone levels of the thyroid and adrenal gland were normal. Testicular ultrasound showed undescended bilateral testis at the inner inguinal ring. Cranial magnetic resonance imaging showed widening of the bilateral frontal horns with concomitant narrowing of the occipital horns of the lateral ventricles, patent cavum septum pellucidum, widening of the bilateral subarachnoid space over the frontal temporal convexity with tortuous bridging vessels, a pituitary gland of 3.1 mm and dysgenesis of the corpus callosum. Cardiac ultrasound showed a normal structure and function of the heart. Ophthalmic examination and hearing screening were generally normal.

His karyotype was 46,XY,inv(9)(p11q12), and the SRY gene could be detected by DNA sequencing. Whole-exome sequencing showed a CHD4 gene mutation (NM_001273): c.3385G>A, p.G1129R, which was not found in his parents. We know that the site is located in the helicase C-terminal domain of the protein and is highly conserved in many species. Three online software programs (SIFT, PolyPhen-2, MutationTaster) predicted the mutant site to be pathogenic, and HOPE software (https://www3.cmbi.umcn.nl/hope/report/62e4f0852810ed052c2cc3c1/) predicted that the mutation could change the structure of the protein. A variation at this site was not found in any of the databases, including ClinVar, HGMD, SNP, 1000 Genomes, and ExAC. According to the American College of Medical Genetics and Genomics (ACMG) variant criterion (PS2+PM1+PM2+PP2+PP3), the mutation was classified as pathogenic. The manifestations of this patient were in line with the main phenotypes and genotype of Sifrim–Hitz–Weiss syndrome (SIHIWES).

During the treatment and follow up, we found that his right testis had descended into the scrotum and that his scrotum was larger than the baseline after the hCG test. Then, we continued with hCG treatment (1000 U, every other day) for 2 months and oral testosterone undecanoate (10 mg, three times a day) for another 3 months following hCG treatment. The patient was last followed up at 4.75 years of age; his most recent height was 104 cm (–1.25 SD), and his weight was 17.4 kg (−0.25 SD). Physical examination showed that the child's extremities were still weak but he could walk independently. His penis grew to 3.5 cm × 1.5 cm, and his right testicle was approximately 2 mL and palpable in the scrotum.

Sifrim–Hitz–Weiss syndrome was first summarized by Sifrim and his colleagues¹ from a group of congenital heart disease patients with CHD4 gene mutations. It is a neurodevelopment syndrome involving multiple systems. Its clinical manifestations include multiple non-specific features, such as global developmental delay, brain structure abnormalities, congenital heart disease, skeletal anomalies, ophthalmic abnormalities, hearing impairment, gonadal abnormalities, and distinctive facial features.² The main phenotypes of SIHIWES were present in this case, and some previously unreported features were found, such as eversion of the lateral third of the lower eyelid and an ape palmprint, which could potentially be additional phenotypes of this syndrome. Unfortunately, the parents of the patient declined permission to publish images of these features.

Regarding the cause of SIHIWES, the CHD4 protein is an important member of the nucleosome recombination and deacetylase (NuRD) complex, an epigenetic regulator that is involved in regulating cell differentiation and proliferation through histone deacetylation, nucleosome recombination and recruitment of transcription factors. It plays an important role in the inhibition of development-related gene expression and the regulation of cell growth.³ Animal experiments have shown that Chd4 is widely expressed in mouse embryos, especially in the central nervous system and the genitourinary system. Homozygous Chd4 knockout mice were embryonic lethal, while heterozygous mice showed growth retardation, abnormal brain waves, dyskinesia, heart malformation and eye abnormalities, similar to the human phenotype.⁴ The main structural domains of the protein include a CHDNT domain, two PHD-zinc domains, two Chromo domains, one SNF_N domain, and one helicase C terminal domain. At present, most reported mutations in the CHD4 gene are non-inherited missense mutations, mainly present in the SNF_N domain and helicase-C-terminal domain of the protein.⁵ Our study identified a de novo variant of the CHD4 gene, which is located in the hotspot variant area. This type of variant was found to be mainly pathogenic in previous studies, supporting the diagnosis of SIHIWES based on the ACMG recommendations.

Sifrim–Hitz–Weiss syndrome is a newly recognized syndrome without clear diagnostic criteria. There is no specific, prominent clinical phenotype or a combination of phenotypes that defines the disease; in particular, the clinical manifestations of the syndrome are not specific, which makes the diagnosis more difficult. There is therefore an urgent need to summarize the characteristics and formulate diagnostic criteria for this disease. Meanwhile, we recommend that patients with SIHIWES-like phenotypes undergo genetic testing to aid diagnosis.

There is no specific treatment except symptomatic treatment, such as providing hCG and testosterone undecanoate to treat the micropenis and cryptorchidism and follow the patients closely. Clinicians should monitor patients’ heights serially during follow up. At present, this child is 4.75 years old without a significant growth delay, but we find that the growth z score has begun to decline compared with that at birth (z score from −0.33 to −1.25). If the height SD is lower than –2 SD, growth hormone may be needed but its effect and side effects need to be studied further.

CONSENT FOR PUBLICATION

Informed written consent was obtained from the patient's parents for the publication of this case report.

CONFLICT OF INTEREST

Chunxiu Gong is a member of the Pediatric Investigation editorial board.