Wolf-Hirschhorn Syndrome
A fetal male was followed by Maternal-Fetal medicine throughout gestation after several notable findings appeared on prenatal ultrasonography, despite normal results from prenatal laboratory screenings for trisomy 13, 18, and 21. The fetus was noted to have right club foot, echogenic bowel, increased ventricular fluid, and hypoplastic cerebellar vermis with indications of Dandy-Walker variation. At 37.5 weeks of gestation, the fetus was noted to have cessation of bone growth. Shortly after this was observed, membranes spontaneously ruptured and the boy was born at 37.5 weeks of gestation. At birth, he weighed 2041 g and was 18 inches in length.
Upon physical examination, 4 abnormalities were noted: submucosal cleft palate, micrognathia (Figures 1A and 1B), hypospadias (Figure 2), and right club foot (Figure 3). A series of tests was conducted, including ultrasonography of the brain, abdomen, and spinal canal, in addition to a chromosomal analysis. Results included a possible hypoplastic cerebellar vermis, an 8 mm filar cyst just inferior to the conus medullaris, and a 6.12 Mb deletion involving chromosome 4p16.3-4p16.1 region, including WHSC1 and WHC2 genes. Based on these findings, the neonate was diagnosed as having Wolf-Hirschhorn syndrome.
DISCUSSION
Wolf-Hirschhorn syndrome is a complex genetic disorder that involves varying degrees of gene deletion from the terminal portion of the short arm of chromosome four.1,2 It occurs in 1:50,000 live births with a female to male ratio of 2:1. However, it is thought that the syndrome may be more common due to misdiagnosis, as some patients experience few phenotypic features and may receive a diagnosis of developmental delay.
Secondary to the large variation of genetic deletion, there is a sizeable variation in phenotypic expression.3 However, loss of genetic material within the 4p16.3 region is essential for an individual to show core phenotypic features.1 Phenotypic expression includes craniofacial findings of “Greek helmet” facial features, cleft lip and/or cleft palate, hypertelorism, low-set ears, micrognathia, short philtrum, and short stature. WHS is also known to involve growth and mental retardation, congenital heart defects (~50%), hearing loss (> 40%; mostly conductive), urinary tract malformations (25%), structural brain abnormalities (33%), seizures (90%-100%), skeletal anomalies (60%-70%), dental defects, feeding difficulties, and visual complications.3,4 All individuals with growth deficiency diagnosed prenatally will also experience muscle underdevelopment with hypotonia, in addition to varying degrees of natal growth retardation.4
Club foot, also known as congenital talipes equinovarus, is one of the most common musculoskeletal birth defects, occurring in 1:1,000 live births.5 Hypospadias is another common congenital anomaly, but when club foot and hypospadias occur together in the same child, underlying chromosomal abnormalities must be ruled out.
Stephen Noorlander, MD, is a 2016 graduate of Ross University School of Medicine in Portsmouth, Dominica.
Fidelina Baraceros, MD, FAAP, is a pediatrician in private practice at Bloomfield Hills Pediatrics in Bloomfield Hill, Michigan.
References
1. Anderson EF, Carey JC, Earl DL, et al. Deletion involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf-Hirschhorn Syndrome. Eur J Hum Genet. 2014; 22(4): 464-470.
2. Mass NM, Van Buggenhout GV, Hannes F, et al. Genotype-phenotype correlation in 21 patients with Wolf-Hirschhorn syndrome using high resolution array comparative genome hybridization. J Med Genet. 2008;45(2):71-80.
3. Battaglia A, Carey JC, Wright TJ. Wolf-Hirschhorn (4p-) syndrome. Adv Pediatr. 2001;48:75-113.
4. Battaglia A, Carey JC, South ST. Wolf-Hirschhorn syndrome. Pagon RA, Adam MP, Ardinger HH, et al, eds. In: GeneReviews. Seattle, WA: University of Washington, Seattle, 1993-2016.
5. Dobbs M, Gurnett C. Update on clubfoot: etiology and treatment. Clin Orthop Relat Res. 2009;467(5):1146-1153.