Wolf-Hirschhorn Syndrome - Causes, Symptoms, and Diagnosis

Introduction

Wolf-Hirschhorn Syndrome is a genetic condition manifesting in multiple areas of the body. The most commonly affected regions are the face, heart, brain, and stature. The disease can be diagnosed due to mild or overlapping symptoms with other diseases. The treatment is symptomatic and unique to the affected individual.

What Are the Causes of Wolf-Hirschhorn Syndrome?

The condition occurs due to the deletion of chromosomes at the end of the short arm (p) at chromosome 4. The condition is also known as 4p syndrome. The deletion of chromosomes happens after fertilization in the majority of cases. The large deletions in chromosome 4 cause severe intellectual and physical disabilities. The genes NSD2 (Nuclear Receptor Binding SET Domain Protein 2), LETM1 (Leucine Zipper And EF- Hand Containing Transmembrane Protein 1), and MSX1 (Msh Homeobox 1, protein-coding gene) are deleted most often causing various signs and symptoms in the affected individual. Deletion of the NSD2 gene is responsible for characteristic facial appearance and delays in development. LETM1 gene deletion causes seizures and abnormal activity in the brain. Deletion of the MSX1 gene causes dental anomalies like cleft lip and palate. Few patients show chromosomal rearrangements that are responsible for varying symptoms among affected individuals. Ring chromosomes (chromosome breaks at two regions and the ends fuse to form a circle resulting in loss of a part of chromatic information) occur in a small percentage of patients.

The disease is not an inherited condition but in some instances, it is inherited from parents without Wolf-Hirschhorn disease (balanced translocation). The condition is more pronounced among women than men. The incidence of the disease is 1 in every 50,000 new births in the United States.

What Are the Features of Wolf-Hirschhorn Syndrome?

The symptoms can appear early in the first trimester of pregnancy or in newborns. The condition affects many body parts and commonly presents with a characteristic facial appearance, delayed growth and development, and intellectual disability. The facial features in the disorder are described as a “Greek warrior helmet” due to the presence of a flat, broad nasal bridge and high forehead.

1. Facial Features - Eyes are widely spaced and appear protruding. A shortened distance between the nose and upper lip is seen. A downturned mouth, small chin (micrognathia), poorly formed ears with small holes, skin tags, and asymmetrical facial features with a small head (microcephaly) are some of the common clinical features of the disease. Slow growth at birth causes problems in infants with feeding and gaining weight. Most patients may require tube feeding at some point that is prolonged for a lifetime.

2. Delayed Growth - There is a significant delay in developing motor skills like sitting, walking, and standing. Weak muscle tone and underdeveloped muscles are present. Children or adults may have shorter stature.

3. Intellectual Disability - The intellectual disability can be of mild to severe intensity. The affected individuals have strong socialization skills but weaker verbal communication and language skills. The patients struggle with quantitative reasoning. Few patients who develop seizures are unresponsive to treatment. The symptom of seizures regresses with age.

4. Skin Changes - Skin changes like mottling (patchy and colored skin) and dryness, skeletal anomalies of scoliosis and kyphosis (abnormal curvature of the spine), dental anomalies of missing teeth, cleft palate, or lip may occur.

5. Eye Abnormality - Abnormalities of eyes like iris coloboma (keyhole defect due to missing tissue), optic atrophy (optic nerve shrinkage), ptosis (drooping eyes), proptosis (bulging eyes), megalocornea (congenital condition of corneal enlargement), and nystagmus (involuntary, rapid and repetitive movement of the eye) may develop. Retinopathy (disease of the retina), sclerocornea (a congenital defect in which the cornea acquires features of sclera), and strabismus (defective eye alignment or crossed eyes) occur occasionally.

6. Heart Defects - Congenital heart defects like an atrial septal defect, abnormal cardiac septal, heart wave, and cardiac system morphology are some of the cardiac symptoms.

Less common features include-

• Some of the least commonly occurring symptoms are hearing loss, urinary tract malformations, structural brain abnormalities, and cerebellar ataxia (poor muscle control causing clumsy voluntary movements). Reduced frequency and strength of fetal movement in the womb can occur.

• Downward slant of palpebral fissures, epicanthus (skin fold in the upper eyelid), high anterior and low posterior hairline, and high-arched eyebrows can occur in a few of the affected individuals.

• Hypospadias (the opening of the penis is in the underside instead of the tip of the penis) and cryptorchidism (undescended testicles), intrauterine growth retardation, low-set posteriorly rotated ears, microtia (poorly formed external ear) and micrognathia (undersized lower jaw), abnormal foot, thorax, and vertebral column morphology, kidney abnormalities are some of the structural anomalies that may occur in the disease.

• In a few patients, aplasia cutis congenita of the scalp (congenital absence of skin on the scalp), aplasia or hypoplasia (undeveloped or underdeveloped) of the lungs, congenital diaphragmatic hernia (a birth defect where a hole occurs in the diaphragm), and recurrent respiratory infections is present.

• Arachnodactyly (long, slender, and curved fingers), calvarial skull defect (skull anomalies due to fracture or neoplasm), and delayed skeletal maturity are some of the skeletal abnormalities.

• Rarely, features of hemangioma (benign tumor of blood vessels), hypoplastic pubis rami (underdeveloped pubis), preaxial hand polydactyly (presence of two thumbs in hand), and rib fusion and segmental abnormalities occur.

• In children, sacral dimples (small dent in the child’s lower back), short hallux (big toe) and thumb, split hand (congenital hand condition causing missing fingers), talipes equinovarus (a birth defect where the foot points downward and inward), and abnormalities of the gut which include malrotation (causes obstruction in the gut), poor movement, and absorption of nutrients can develop.

• Developmental anomalies like tether cord (spinal cord fixed or stuck to the spinal canal), abdominal situs inversus (a congenital disease where chest and abdominal organs are reversed), and abnormalities in the gallbladder, genital system, and immune system are seen. In a few instances, agenesis of corpus callosum (brain disorder where tissue connecting left and right brain are absent) and aplasia or hypoplasia of nipples or hernia (organ pushes through weak muscle or tissue) occurs.

• Pitt-Rogers-Danks syndrome has overlapping features with Wolf-Hirschhorn syndrome as they are part of a similar syndrome but varies in presenting features. The symptoms are milder in Pitt-Rogers-Danks syndrome.

How Is Wolf-Hirschhorn Syndrome Diagnosed?

The following methods can be used to diagnose Wolf-Hirschhorn Syndrome-

• Prenatal diagnosis with expanded cell-free DNA (deoxyribonucleic acid) screening test. The test is useful for screening but is not diagnostic.

• Fluorescence in situ hybridization (FISH) test can identify chromosomal deletions.

• Genetic testing with chromosomal microarray.

• The changes in the affected child’s chromosome are identified by examining blood, saliva, or cheek cells. Abnormalities in chromosomes result in disease confirmation.

• The disease can be suspected based on clinical symptoms including, facial characteristics, growth abnormalities and developmental delays, and seizures.

What Are the Treatment Options for Wolf-Hirschhorn Syndrome?

There is no cure for the disease and treatment is provided to manage significant clinical morbidity. Patients with severe heart or brain abnormalities have reduced life span.

• Surgery is required to repair the heart and other growth abnormalities.

• Muscle tone can be increased with physical or occupational therapy.

• Cognitive abnormalities are managed with educational programs.

• Seizures are treated with medications.

• Speaking devices or sign language is necessary for communication.

• Genetic counseling is necessary for effective symptom management.

What Is the Differential Diagnosis for Wolf-Hirschhorn Syndrome?

• Trisomy: The condition has similar features of growth failure and developmental delays.

• Cri-du-chat Syndrome: Cri-du-chat syndrome is a congenital condition with the deletion of chromosome 5. The overlapping symptoms of poor growth, feeding problems, small head, and intellectual abnormalities appear. In addition, they have respiratory problems and a high, shrill cry.

• Down syndrome is a congenital condition with three copies of chromosome 21. The disease has overlapping symptoms of low muscle tone, small stature, intellectual disability, heart defects, and abnormal gastrointestinal tracts.

• Angelman syndrome occurs due to abnormalities in chromosome 15. The disease exhibits features of severe developmental delay, intellectual disability, speech impairments, movement and posture abnormalities, microcephaly, and seizures.

• William syndrome occurs due to deletion in the long arm of chromosome 7. Patients show mild intellectual abnormality, unique personal characteristics, distinctive facial appearance, and cardiovascular anomalies. Calcium build-up in different areas of the body causes kidney anomalies and digestive issues.

Conclusion

Wolf-Hirschhorn Syndrome is a birth defect seen in fetuses and newborns. The symptoms may vary among affected individuals due to differences in chromosomal deletion. Few patients with mild health defects can live up to adulthood. However, most patients experience significant morbidity and mortality. The disease is treated symptomatically. Further, studies are required for the early detection and management of the disease.