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Year : 2016  |  Volume : 9  |  Issue : 4  |  Page : 531-533  

Wolf-Hirschhorn syndrome presenting with cardiac manifestations at birth

Department of Paediatrics, Dr. DY Patil Medical College, Hospital and Research Centre, Dr. DY Patil Vidyapeeth, Pimpri, Pune, Maharashtra, India

Date of Web Publication12-Jul-2016

Correspondence Address:
Sudhir D Malwade
Department of Pediatrics, Dr. D. Y. Patil Medical College and Research Centre, Pimpri, Pune, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0975-2870.186060

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Wolf–Hirschhorn syndrome (WHS) is a condition of developmental delay and dysmorphology caused by a deletion of short arm of chromosome 4. The main characteristics of WHS are intra and extrauterine growth retardation, mental retardation with typical facial dysmorphism, microcephaly, and midline fusion defects. The diagnosis is based on clinical features and chromosomal analysis, e.g., microsatellite analysis or molecular cytogenetic techniques and fluorescence in situ hybridization (FISH) to detect the deletion. Prenatal diagnosis is possible by FISH. Though no specific treatment is available, supportive management can be fruitful. Here, we describe a female baby with a 4p deletion, who had the majority of the main phenotypic features of WHS and severe congenital heart disease manifesting at birth. The case emphasized that any fetus with intrauterine growth retardation, dysmorphic features on antenatal scan, and midline defects should raise a suspicion of WHS. Conventional cytogenetic studies can miss the diagnosis; hence, these cases should be further investigated using molecular cytogenetic techniques such as FISH or array-comparative genomic hybridization.

Keywords: Congenital heart defects, deletion, Wolf–Hirschhorn syndrome chromosome 4

How to cite this article:
Malwade SD, Agarkhedkar S, Swapnil. Wolf-Hirschhorn syndrome presenting with cardiac manifestations at birth. Med J DY Patil Univ 2016;9:531-3

How to cite this URL:
Malwade SD, Agarkhedkar S, Swapnil. Wolf-Hirschhorn syndrome presenting with cardiac manifestations at birth. Med J DY Patil Univ [serial online] 2016 [cited 2023 Feb 1];9:531-3. Available from:

  Introduction Top

The Wolf–Hirschhorn syndrome (WHS) is a well-known, multiple congenital malformation syndrome, which affects 1 in 50,000 live births with a 2:1 female:male ratio.[1],[2] It is caused by a partial loss of genetic material from the distal portion of the p arm of chromosome 4. It is a contiguous gene syndrome with complex and variable variety of clinical features ranging from pre- and post-natal growth retardation, low birth weight (LBW) (77%), developmental delay, microcephaly (90%), characteristic craniofacial appearance described as “Greek warrior helmet,”[3],[4] which consists of high forehead, prominent glabella, hypertelorism, high-arched eyebrows, broad nasal bridge, protruding eyes, epicanthal folds, short philtrum, downturned corners of mouth, micrognathia, and often seizures [3] (50-85%), with mild to severe mental retardation (75%) and hypotonia (90%). Associated congenital anomalies include midline fusion defects (cleft lip/palate, hypospadias), renal anomalies such as dysplastic kidney (23%), congenital heart disease (31-45%), skeletal abnormalities, and ophthalmic anomalies like iris coloboma (30%).

Most of the patients with WHS have a de novo deletion (85% of cases), usually on the paternal chromosome while the rest are familial translocations. Mutations in MEX1 gene are responsible for most of the facial features and deletions in WHS critical region 1 and WHS critical region 2 often manifest as commonly described phenotypic features of the syndrome.[5]

The severity of the clinical manifestations depends on the size of the deletion. There is no concrete information on life expectancy, almost one-third of patients die in the 1st year of life due to pneumonia or congestive heart disease.[6]

  Case Report Top

A term female baby was born vaginally with a breech presentation to a nonconsanguineously married, gravida five mother with an uneventful pregnancy. The birth weight was 1.5 kg (<10 centiles), birth length 42 cm (<10 centiles) and head circumference 30 cm (<10 centiles). The baby was resuscitated as she did not cry immediately after birth. The Apgar score at 1 min was 6 and at 5 min was 7. The child was shifted to Neonatal Intensive Care Unit (NICU) in view of perinatal depression and LBW care. On admission, the baby was hypothermic and had respiratory distress.

A chest radiograph was suggestive of hyaline membrane disease, and surfactant was proposed but denied by unaffording parents. Complete blood count and septic screen were normal. The initial management in NICU included administration of continuous positive air pressure (CPAP) for maintenance of oxygen saturation, stabilization of temperature and optimal maintenance of glucose and blood pressure.

The examination revealed severe hypotonia and dysmorphic features such as microcephaly, high forehead, prominent glabella, hypertelorism, depressed nasal bridge, short philtrum, protruding eyes, cleft palate, low set ears, micrognathia, and down turned corners of mouth [Figure 1]. A Grade 4 systolic murmur and a 2 cm palpable liver were present.
Figure 1: Picture of the baby showing high forehead, low set ears, down turned corners of mouth

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CPAP and inotropic support were gradually weaned off with improvement in clinical condition and feeding was commenced. The further clinical course consisted of waxing and waning oxygen requirements, fluctuating blood pressures, blood sugars, and feeding difficulties. In view of dysmorphic-clinical features, hypotonia and heart abnormality, laboratory investigations were organized, which included a CPK-MB, chromosomal analysis, echocardiography, and cranial as well as abdominal ultrasound.

Two-dimensional echocardiogram revealed congenital acyanotic heart disease with large atrial septal defect (ASD) of 9 mm with left to right shunt, dilated right atrium, and right ventricle, severe pulmonary hypertension with mild tricuspid regurgitation and signs of cardiac failure, which led to the addition of furosemide and an angiotensin-converting enzyme inhibitor enalapril in the treatment. The cranial ultrasound showed mild lateral ventriculomegaly whereas ultrasound abdomen was normal. Karyotyping showed deletion of chromosome 4 at band 4p15.2 consistent with WHS [Figure 2]. The laboratory used G bands by Trypsin and Giemsa banding technique.
Figure 2: Chromosome analysis showing deletion of chromosome 4 at band 4p15.2

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During the 2nd week of hospitalization, the baby started deteriorating with signs of progressive respiratory failure. Chest radiograph at this stage was, suggestive of cardiomegaly and evolving chronic lung disease. Steroids were started according to chronic lung disease regime. The condition of the baby deteriorated further and due to the unwillingness of parents for further support baby succumbed on 27th day of life secondary to respiratory failure due to congestive heart failure.

  Discussion Top

WHS, was first described in 1961 by Cooper and Hirschhorn [7] and, thereafter, by the German Ulrich Wolf,[8] and it has a characteristic phenotype resulting from a partial deletion of chromosomal material of the short arm of chromosome 4.[9]

Phenotype expression depends on the size of the deletion of the chromosome.[10],[11] Patients with large deletions (breakpoint distal to and including p15.2) are usually more affected, with severe developmental delay, mental retardation, microcephaly, heart defects, midline defects, kidney abnormalities, and seizures. Patients with microdeletions (p15.3-p16.3) have milder phenotypic changes, usually without congenital malformations, with microcephaly, developmental delay, typical facial appearance, and mild hypotonia. There is a statistically significant relationship between deletion size and the overall risk of death in de novo deletion cases.[1]

Initial diagnosis is based on characteristic phenotypic features and should be confirmed with genetic testing. Routine karyotyping can miss the diagnosis and advanced genetic testings such as microsatellite analysis or molecular cytogenetic techniques are needed to confirm or exclude the diagnosis.

As discussed, our case involved a large de novo deletion (4p15.2). It was an intrauterine growth restriction female with most of the facial features consistent with the standard description of WHS in literature. Hypotonia, feeding difficulties, and midline defects (ASD, cleft palate and a ventriculomegaly) were presented that support the diagnosis of WHS. Cardiac manifestations are seen in 31-45% of the cases and are responsible for nearly 35% of the deaths in the 1st year of life,[1] which was evident in our case as well. Cases have been reported in literature, of survival with a variable degree of mental retardation and other associated abnormalities. Though our case involved a de novo deletion with no past similar incidence in the family, nevertheless parents were counseled regarding the next pregnancy.

  Conclusion Top

WHS presents with a constellation of signs and symptoms, which include mental retardation, seizures, hypotonia, feeding difficulties, and a range of midline fusion defects. A high index of suspicion should be present in babies with congenital anomalies, phenotypic dysmorphism, and midline defects with multisystem involvement. Genetic testing is available for diagnosis and antenatal diagnosis by fluorescence in situ hybridization can be done.

Its association with profound mental retardation and severe morbidity highlights the importance of prenatal diagnosis. Prognosis is poor with no definitive treatment though patients can be managed with multidisciplinary supportive measures.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


The authors thank the family for their participation in the study. We also thank the hospital staff for their cooperation to collect the data.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Shannon NL, Maltby EL, Rigby AS, Quarrell OW. An epidemiological study of Wolf-Hirschhorn syndrome: Life expectancy and cause of mortality. J Med Genet 2001;38:674-9.  Back to cited text no. 1
Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, et al. Mapping the Wolf-Hirschhorn syndrome phenotype outside the currently accepted WHS critical region and defining a new critical region, WHSCR-2. Am J Hum Genet 2003;72:590-7.  Back to cited text no. 2
Battaglia A, Filippi T, Carey JC. Update on the clinical features and natural history of Wolf-Hirschhorn (4p-) syndrome: Experience with 87 patients and recommendations for routine health supervision. Am J Med Genet C Semin Med Genet 2008;148C:246-51.  Back to cited text no. 3
Pitt DB, Rogers JG, Danks DM. Mental retardation, unusual face, and intrauterine growth retardation: A new recessive syndrome? Am J Med Genet 1984;19:307-13.  Back to cited text no. 4
Paradowska-Stolarz AM. Wolf-Hirschhorn syndrome (WHS) — literature review on the features of the syndrome. Adv Clin Exp Med 2014;23:485-9.  Back to cited text no. 5
Heljic S, Had'agic-Catibušic F, Maksic H, Terzic S, Dozic M, Mackic M, et al. Wolf-Hirschhorn syndrome: Report of two cases in Bosnia and Herzegovina. BJMG 2007;10/2:77-80.  Back to cited text no. 6
Cooper H, Hirschhorn K. Apparent deletion of short arms of one chromosome (4 or 5) in a child with defects of midline fusion. Hum Chrom News 1961;4:14-6.  Back to cited text no. 7
Wolf U, Reinwein H, Porsch R, Schröter R, Baitsch H. Deficiency of the short arms of a chromosome No 4. Humangenetik 1965;1:397-413.  Back to cited text no. 8
Battaglia A, Carey JC, Wright TJ. Wolf-Hirschhorn (4p-) syndrome. Adv Pediatr 2001;48:75-113.  Back to cited text no. 9
Quarrell OW, Snell RG, Curtis MA, Roberts SH, Harper PS, Shaw DJ. Paternal origin of the chromosomal deletion resulting in Wolf-Hirschhorn syndrome. J Med Genet 1991;28:256-9.  Back to cited text no. 10
Wieczorek D, Krause M, Majewski F, Albrecht B, Horn D, Riess O, et al. Effect of the size of the deletion and clinical manifestation in Wolf-Hirschhorn syndrome: Analysis of 13 patients with a de novo deletion. Eur J Hum Genet 2000;8:519-26.  Back to cited text no. 11


  [Figure 1], [Figure 2]


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