Wolf-Hirschhorn Syndrome

Original Editor - Rucha Gadgil
Top Contributors - Rucha Gadgil and Lucinda hampton

Introduction

Wolf–Hirschhorn syndrome (WHS), is a chromosomal deletion syndrome resulting from a partial/ complete deletion on the short arm of chromosome 4 (4p16.3), also called the Wolf–Hirschhorn critical region (WHCR). It was first described in 1961 by Hirschhorn and subsequently in 1965 by Wolf, and is known as the first example of a classic human chromosomal deletion syndrome. It is characterised by severe prenatal findings and confirmatory genetic testing, and is mainly described by isolated cases and case series.

It is also known as Wittwer syndrome, chromosome 4p16.3 deletion syndrome, Pitt-Rogers-Danks syndrome or Pitt syndrome. The syndrome is characterized by “Greek warrior helmet” facies, microcephaly, seizure disorder, closure defects (coloboma, cleft lip or palate, and cardiac defects), and growth and intellectual disability . There is a wide variation in phenotypic expression which can be explained by the size of the deletion.

The incidence is reported as 1 in 50,000 cases and occurs more frequently in females (2:1).

Etiology

A deletion in the short arm of chromosome 4 with contribution of genes within a 1.5-1.6 Mb region in the ~0.4-1.9 Mb terminal of 4p16.3 causes WHS. Deletions greater than 3-5 Mb contribute to a higher risk of heart defects and cleft palate.

The genetic mechanisms can be:

1. 50%-60% of individuals with WHS have a de novo pure deletion of 4p16
2. 40%-45% have an unbalanced translocation with both a deletion of 4p and a partial trisomy of a different chromosome arm. The unbalanced translocations may be de novo or inherited from a parent by balanced rearrangement.
3. complex rearrangements leading to a 4p16.3 deletion (e.g., ring 4).

Hereditary carriers depend on the mechanism of origin of the deletion. Prenatal testing in which one parent is known to be a carrier of a chromosome rearrangement involving 4p16.3 is always advised.

Clinical Presentation

WHS is a rare condition, characterized by severe prenatal onset growth restriction, typical facial features, and severe seizures.

The typical craniofacial features in infancy consist of:

• "Greek warrior helmet" appearance of the nose (wide bridge of the nose continuing to the forehead),
• microcephaly,
• high anterior hairline with prominent glabella,
• widely spaced eyes, epicanthus,
• highly arched eyebrows, short philtrum, downturned corners of the mouth, micrognathia,
• and poorly formed ears with pits/tags.

Other features include:

• significant prenatal-onset growth deficiency followed by postnatal growth retardation
• hypotonia with muscle underdevelopment
• Developmental delay/intellectual disability of variable degree, and structural brain abnormalities (33%).
• Epileptic seizures (90% to 100% )/ abnormal EEG findings
• skeletal anomalies (60%-70%),
• congenital heart defects (~50%),
• hearing loss (mostly conductive) (>40%),
• urinary tract malformations (25%).
• feeding difficulties

Diagnostic Procedures

WHS can be diagnosed based on:

• Suggestive findings: the clinical features described above
• Confirmed by Genetic testing by:

1. Chromosomal microarray (CMA) using oligonucleotide arrays or SNP genotyping arrays.
2. Conventional G-banded cytogenetic studies detecting a deletion in the distal portion of the short arm of one chromosome 4 involving band 4p16.3.
3. Targeted deletion analysis. FISH analysis may be used in individuals with clinical features.

Differential Diagnosis

WHS should be differentially diagnosed from:

• Proximal 4p deletion. it is disorder is a discrete syndrome, distinct from WHS.
• WHS phenotype: features may overlap with the following disorders:

1. Seckel syndrome : inherited in an autosomal recessive manner and is caused by biallelic pathogenic variants in one of the following genes: ATR, NIN, ATRIP, RBBP8, CEP152, CENPJ, or CEP63.
2. CHARGE syndrome is inherited in an autosomal dominant manner; however, most individuals diagnosed with CHARGE syndrome represent simplex cases.
3. Smith-Lemli-Opitz syndrome (SLOS) is caused by an abnormality in cholesterol metabolism resulting from deficiency of the enzyme 7-dehydrocholesterol reductase.
4. Opitz G/BBB syndrome
5. Malpuech syndrome: is inherited in an autosomal recessive manner.
6. Lowry-MacLean syndrome
7. Williams syndrome (WS) is inherited in an autosomal dominant manner; however, most individuals diagnosed with WS represent simplex cases.
8. Classic Rett syndrome
9. Angelman syndrome (AS) is caused by disruption of maternally imprinted UBE3A located within the 15q11.2-q13 Angelman syndrome/Prader-Willi syndrome (AS/PWS) region.
10. Smith-Magenis syndrome (SMS) is caused by deletion of or a heterozygous pathogenic variant in RAI1 on chromosome 17p11.2. Virtually all individuals diagnosed with SMS represent simplex cases.

Outcome Measures

The outcome measured used in WHS are based on the clinical signs and symptoms and differ according to each case.

1. BERA for auditory features
2. Quality of life outcome measures (for individuals and caregivers)

Management / Interventions

The management of WHS includes a multi-disciplinary team depending upon the extent of disease and needs in an individual. The individual diagnosed with WHS needs to be assessed and evaluated based on:

• Their growth parameters , cognitive, language, and motor development and social skills
• Waking/sleeping video-EEG-polygraphic studies in childhood (mainly ages 1-6 years) to detect atypical absence seizures
• feeding problems and gastroesophageal reflux
• Physical examination for skeletal anomalies (e.g., clubfoot, scoliosis, kyphosis);
• Ophthalmology consultation
• Cardiac evaluation
• Complete blood count to evaluate for hematopoietic dysfunction
• Comprehensive evaluation by an otolaryngologist and comprehensive audiologic screening (brain stem auditory evoked responses)
• Renal function testing and renal ultrasonography in infancy to detect structural renal anomalies and/or vesicoureteral reflux
• Baseline liver ultrasound to evaluate for hepatic adenoma

Medical Management

The interventions should be individualised based on the findings and reports.

The medical management mainly looks towards:

• Seizures: Appropriate medication based on the type of seizure can be given by the neurophysician.
• Ophthalmologic abnormalities , and Congenital heart defects are usually treated medically and surgically wherever required.
• Hepatic adenomas. Medical treatment (either surgery or chemotherapy) varies in relation to the number and size of the adenomas.
• Antibiotic prophylaxis is indicated for vesicoureteral reflux. Intravenous Ig infusions or continuous antibiotics may be indicated for those with antibody deficiencies.
• Systematic surveillance is recommended by doing:

1. Complete blood count annually to evaluate for hematopoietic dysfunction
2. Annual renal function testing, including serum BUN, creatinine, and cystatin C; urinalysis; and creatinine clearance test
3. Consideration of routine liver ultrasonography to evaluate for liver adenomas

Genetic Counselling is recommended in cases where hereditary factor is observed.

Physiotherapy Management

Individuals are treated according to the signs and symptoms that they present.

Skeletal and movement abnormalities (e.g., clubfoot, scoliosis, kyphosis) needs intervention : ROM exercises, NDT, strengthening, balance and mobilization can be given.

Learning difficulties: Physiotherapists can work in conjunction with the occupational therapists to make the child functionally independent.

Feeding difficulties. oro-motor therapy can be recommended.

Physiotherapy treatment will mainly work towards developing postural control and gaining developmental milestones.

There are limited studies documenting the physiotherapy treatments in WHS.