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Wolf Hirschhorn Syndrome

Wolf-Hirschhorn Syndrome

Wolf-Hirschhorn syndrome (WHS) is a very rare congenital disorder resulting from a partial deletion of the short arm of chromosome 4. It is found in approximately 1 in 50,000 births and is characterized by intrauterine growth restriction, broad nose, microcephaly, growth and mental deficiency, heart defects, ocular hypertelorism. The presentation of this syndrome, however, varies depending on the extent of genetic material deleted. The longer the extent of the deletion, the more severe the disease.


Presentation

Wolf–Hirschhorn syndrome affects many parts of the body. The most common features are the abnormal facies, jaw abnormalities, seizures, and intellectual impairment. Greek warrior helmet appearance is the typical craniofacial abnormality seen in WHS that includes prominent glabella, hypertelorism, broad nasal bridge, micrognathia and microcephaly, high-arched eyebrows, short philtrum, poorly formed ears, epicanthus and down turned mouth.

Skeletal abnormalities such as club feet, fused ribs, proximal radioulnar synostosis, hip dislocationscoliosis, and kyphosis occur in up to 70% of cases. Anatomic brain defects are seen in 33% of cases. Congenital heart defects in 50%, conductive hearing loss in 40% and urinary tract defects such as hypospadias are seen in about 25% of the cases.

Prenatal and postnatal growth retardation along with hypotonia and muscle development is seen in all individuals having WHS. Undescended testes and precocious puberty are common occurrences in patients with WHS.

The eye findings characteristic to WHS include ptosis, strabismus, iris deformity, slanted eyelid slits, epicanthic folds, and coloboma. Defects may also be seen in the middle half of the eyebrow. In the hands, notable features include dermal ridges, simian crease in the palms, and hyperconvex nails. There may also be permanently plantarflexed feet impeding ambulation. 

The most constant features of WHS are the facial features, intellectual involvement, growth retardation, and failure to thrive. The intellectual impairment, however, varies in severity in the patients. Motor functions of the brain, such as walking and standing are considerably impaired and these patients usually have short stature. In these patients, however, social skills are not as impaired as verbal and language skills.

Seizures are seen in 50% - 100% of WHS and are usually recalcitrant to treatment. The seizures may resolve spontaneously as the child grows older. Generally in WHS, EEG abnormalities are seen in over 90% of cases, making this a diagnostic factor in WHS [11].

Multiple Congenital Anomalies
  • The present case shows that not only deletions but also duplications of the Wolf-Hirshhorn critical region cause mental retardation and multiple congenital anomalies.[ncbi.nlm.nih.gov]
  • Examination with two- and three-dimensional ultrasonography is useful to observe the face of fetuses with severe intrauterine growth restriction to diagnose multiple congenital anomaly syndromes.[ncbi.nlm.nih.gov]
  • We report on a 16-month-old male patient with ring chromosome 4 and deletion of Wolf-Hirschhorn syndrome (WHS) region with multiple congenital anomalies including unilateral cleft lip and palate, iris coloboma, microcephaly, midgut malrotation, hypospadias[ncbi.nlm.nih.gov]
  • INTRODUCTION: Wolf-Hirschhorn syndrome (WHS) multiple congenital anomalies/mental retardation is caused by partial deletion of the short arm of chromosome 4 and can be considered a contiguous gene syndrome, characterized by typical facial appearance,[ncbi.nlm.nih.gov]
  • Wolf-Hirschhorn syndrome (WHS) is a rare chromosomal disorder characterized by facial dismorphy, multiple congenital anomalies, delayed psychomotor development and pharmaco-resistant epilepsy.[ncbi.nlm.nih.gov]
Single Transverse Palmar Crease
  • [ncbi.nlm.nih.gov] Single Transverse Palmar Crease transverse palmar crease , broad hands, fifth digit clinodactyly), joint hyperflexibility, redundant neck skin, pelvic dysplasia, wide gap between first and second toes (sandal gap), short stature GI[symptoma.com]
  • transverse palmar crease, broad hands, fifth digit clinodactyly), joint hyperflexibility, redundant neck skin, pelvic dysplasia, wide gap between first and second toes (sandal gap), short stature GI : duodenal and anorectal atresia, umbilical hernia[pathophys.org]
Poor Feeding
  • It might be caused by genetic factors, poor feeding status, inherited parental factors and associated diseases. Whether patients with WHS suffer from an additional endocrine disorder is not known and is beyond the scope of this study.[dx.doi.org]
Periodontitis
  • At the beginning, bad dental and periodontal conditions with gingival signs and recurrent mucosal inflammation were found in all patients.[ncbi.nlm.nih.gov]
Hyperconvex Nails
  • [ncbi.nlm.nih.gov] Skin Hyperconvex Nails In the hands, notable features include dermal ridges, simian crease in the palms, and hyperconvex nails . There may also be permanently plantarflexed feet impeding ambulation.[symptoma.com]
  • In the hands, notable features include dermal ridges, simian crease in the palms, and hyperconvex nails. There may also be permanently plantarflexed feet impeding ambulation.[symptoma.com]
Hearing Impairment
  • Analysis of patients with chromosomal rearrangements represents one strategy toward identifying candidate genes for genetic hearing impairment.[ncbi.nlm.nih.gov]
  • [symptoma.com] Ears Hearing Impairment Analysis of patients with chromosomal rearrangements represents one strategy toward identifying candidate genes for genetic hearing impairment .[symptoma.com]
  • Other significant problems can include heart defects, cleft lip and/or palate, hearing impairment, and eye problems. Most children who have WHS have seizures (approximately 90%). Seizures are one of the major health concerns in children with WHS.[wolfhirschhorn.org]
  • Histopathological basis of hearing impairment in Wolf-Hirschhorn syndrome.[ncbi.nlm.nih.gov]
Cranial Asymmetry
  • asymmetry Droopy eyelids Dental abnormalities DImple at the base of spine Aside from the possibly physical properties due to Wolf-Hirschhorn syndrome, patients diagnosed with this disease may also experience: Intellectual disability Severe retardation[wiki.ggc.edu]
  • Heart problems Underdeveloped bones of the head and pelvis Cranial asymmetry Malformation of the organs of the urinary system Malformation of bones in chest and spine Distinctive facial features, such as broad nose and short head, which are collectively[medicalsubstance.com]
  • [wolfhirschhorn.org] Musculoskeletal Cranial Asymmetry Heart problems Underdeveloped bones of the head and pelvis Cranial asymmetry Malformation of the organs of the urinary system Malformation of bones in chest and spine Distinctive facial features,[symptoma.com]
  • asymmetry), skin tag or pit in front of the ear (preauricular tag or pit), prominent triangular area of the forehead (glabella), scalp defects on the center of the back of the head, underdeveloped fingerprints (dermal ridges), a single crease across[flipper.diff.org]
  • asymmetry) skin tag or pit in front of the ear (preauricular tag or pit) downturned mouth prominent triangular area of the forehead (glabella) scalp defects on the center of the back of the head underdeveloped fingerprints (dermal ridges) a single crease[wolfhirschhorn.org]
Muscle Hypotonia
  • Generalized muscle hypotonia was observed at birth. First seizures started at age of 9 months as unilateral convulsive status epilepticus (SE), sometimes with bilateral generalization.[ncbi.nlm.nih.gov]
  • hypotonia, seizures, and congenital heart defects.[en.wikipedia.org]
  • Hypotonia Generalized muscle hypotonia was observed at birth.[symptoma.com]
  • It is characterized by mental retardation, microcephaly, seizures, muscle hypotonia, a distinctive facial appearance with prominent forehead and wide set eyes, growth failure with malformations of the spine, hands, and feet, congenital heart defects,[flipper.diff.org]
Lordosis
  • Features that may affect the lower limb include lordosis, scoliosis, hypotonia, talipes equinovarus, and lesser-toe anomalies. This article reviews the literature on this rare syndrome and presents three case studies.[ncbi.nlm.nih.gov]
  • [medcraveonline.com] Lordosis Features that may affect the lower limb include lordosis , scoliosis, hypotonia, talipes equinovarus, and lesser-toe anomalies. This article reviews the literature on this rare syndrome and presents three case studies.[symptoma.com]
Hypertelorism
  • BACKGROUND: Wolf-Hirschhorn syndrome (WHS) is associated with facial dysmorphism including high forehead, high nasal bridge, hypertelorism and severe mental retardation. WHS results from a 4p16.3 deletion.[ncbi.nlm.nih.gov]
  • Opitz G/BBB syndrome (OS) is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay and cardiac defects.[ncbi.nlm.nih.gov]
  • The facial phenotype is characterized by hypertelorism, protruding eyes, prominent glabella, broad nasal bridge and short philtrum.[ncbi.nlm.nih.gov]
  • [ncbi.nlm.nih.gov] Face, Head & Neck Hypertelorism Wolf-Hirschhorn syndrome (WHS) is associated with facial dysmorphism including high forehead, high nasal bridge, hypertelorism and severe mental retardation. WHS results from a 4p16.3 deletion.[symptoma.com]
  • The facial dysmorphic features in the present case were dolichocephaly; high forehead; large rectangular nose continuing to the eyebrows; hypertelorism; short philtrum; carp-shaped mouth; microretrognathia; and large, simply modeled, low-set ears.[ncbi.nlm.nih.gov]
Beaked Nose
  • nose Frontal bossing (See the images below.)[emedicine.medscape.com]
  • [ncbi.nlm.nih.gov] Beaked Nose An autosomal dominant [MIM 194190] chromosome deletion complex characterised by low birth weight, microcephaly, ‘Greek helmet’ facies—micrognathia, hypertelorism, epicanthus, beaked nose , redundant lateral nasal folds,[symptoma.com]
  • Features of the syndrome include midline defects with a scalp defect, widespaced eyes, broad or beaked nose, oral facial clefts ( cleft lip /palate); low simple ears with a dimple in front of the ear; small and/or asymmetrical head; heart defects; and[medicinenet.com]
  • An autosomal dominant [MIM 194190] chromosome deletion complex characterised by low birth weight, microcephaly, ‘Greek helmet’ facies—micrognathia, hypertelorism, epicanthus, beaked nose, redundant lateral nasal folds, cleft palate—inguinal hernia, cryptorchism[medical-dictionary.thefreedictionary.com]
Beak Nose
  • nose Frontal bossing (See the images below.)[emedicine.medscape.com]
  • [ncbi.nlm.nih.gov] Beaked Nose An autosomal dominant [MIM 194190] chromosome deletion complex characterised by low birth weight, microcephaly, ‘Greek helmet’ facies—micrognathia, hypertelorism, epicanthus, beaked nose , redundant lateral nasal folds,[symptoma.com]
  • Features of the syndrome include midline defects with a scalp defect, widespaced eyes, broad or beaked nose, oral facial clefts ( cleft lip /palate); low simple ears with a dimple in front of the ear; small and/or asymmetrical head; heart defects; and[medicinenet.com]
  • An autosomal dominant [MIM 194190] chromosome deletion complex characterised by low birth weight, microcephaly, ‘Greek helmet’ facies—micrognathia, hypertelorism, epicanthus, beaked nose, redundant lateral nasal folds, cleft palate—inguinal hernia, cryptorchism[medical-dictionary.thefreedictionary.com]
Downturned Corners of the Mouth
  • Microcephaly, hypertelorism, prominent glabella, high arched eyebrows, broad nose, short philtrum, downturned corners of the mouth, dysplastic ears with pits/tags. Cleft lip/palate.[genetics4medics.com]
  • corner of the mouth Microcephaly Low-set ears with pits or tags Intrauterine growth restriction (IUGR)/postnatal growth deficiency Hypotonia with decreased muscle bulk Present in 50-75% of patients [6, 14] : Skeletal anomalies - Kyphosis and scoliosis[emedicine.medscape.com]
  • corners of the mouth, micrognathia, and poorly formed ears with pits/tags.[ncbi.nlm.nih.gov]
Seizure
  • Four of these individuals have never had an observable seizure, and the fifth individual had a single febrile seizure at the age of 1.5 years.[ncbi.nlm.nih.gov]
  • The mean age of the last seizure for those who were seizure free for 3 years was 11.3 years (range 2-28 years); in the majority of patients, seizures ceased within childhood years. Many parents commented that seizures were precipitated by fever.[ncbi.nlm.nih.gov]
  • Sixty out of 81 (74%) had generalized tonic-clonic seizures, which was the only seizure pattern in 32. Tonic spasms occurred in 15 out of 81 (18%), complex partial seizures in 10 out of 81 (12%), and clonic seizures in 6 out of 81 (7%).[ncbi.nlm.nih.gov]
  • Based in part on these similarities, we suggest that a highly successful Phase III clinical trial of a formulation of cannabidiol for Dravet syndrome seizures may be directly translatable into possible benefits for WHS individuals with challenging seizure[ncbi.nlm.nih.gov]
  • Two of these, encompassing LETM1, were found in subjects who never had seizures.[ncbi.nlm.nih.gov]

Workup

The characteristic facial features with the seizures and the growth and psychomotor delay suggests a diagnosis of WHS. It is further confirmed by detection of loss of genes on chromosome 4. Ideally, deletion of critical region confirms the diagnosis of WHS.

Fluorescence in situ hybridization (FISH) detects almost 95% of these deletions against 60% detection rate by conventional high resolution G-banded cytogenetic analysis.

More than 55% of patients with WHS have no other genetic abnormality beside these deletions, also called as pure deletion. In the rest, other findings such as 4p-mosaicism or unbalanced translocation resulting in a derivative of chromosome 4 or ring chromosome 4 occurs. The pure deletion forms can be delineated from the other more complex imbalances by chromosomal microarray (CMA). It is more accurate than G-band analysis or FISH. 

Other investigations, serve to check for possible abnormalities associated with WHS. These include radiography to detect the skeletal abnormalities, echocardiography , renal ultrasonography, and MRI/CT scans of the brain. Brain MRI/CT may show underlying brain abnormalities such as agenesis of the corpus callosum and dilated ventricles. ECHO should be done in all the patients to detect heart abnormalities.

Prenatal diagnosis of WHS is made by ultrasonography. However, diagnosis is more accurately made using FISH which detects the abnormality in 95% of the cases. Routine conventional G-banded analysis employed prenatally, confirms the diagnosis in 70% of the cases.

Delayed Bone Age
  • At autopsy, the fetus showed typical craniofacial dysmorphic signs of WHS, severe IUGR and delayed bone age.[ncbi.nlm.nih.gov]
  • X-ray Delayed Bone Age At autopsy, the fetus showed typical craniofacial dysmorphic signs of WHS, severe IUGR and delayed bone age .[symptoma.com]

Treatment

A multidisciplinary approach is required for the management of WHS. Being genetic in nature the treatment of this condition is essentially supportive. It includes, speech or communication therapy, physical rehabilitation, sign language, medical treatment and rehabilitation. Medical treatment includes treating the underlying condition. Antiepileptic drugs such as valproic acid and benzodiazepines are used for managing seizures.

A team approach is required to handle abnormalities like skeletal defects, congenital heart defects, hearing loss and opthalmologic abnormalities. The feeding difficulties are managed with gavage feeding or gastrostomy. Surgical correction is required in cases with cleft lip and palate. Helping the child to reach his full potential is important and can be achieved with teamwork.

Prognosis

Wolf-Hirschhorn syndrome is often associated with intrauterine deaths, still births and infant mortality. In children who survive beyond the first year of life usually have slow but constant development. Mental retardation and severe intellectual impairment are often complications of WHS. 

Etiology

Wolf-Hirschhorn syndrome (WHS) is the result of a partial deletion of the short arm of chromosome 4. Various changes can occur in the chromosome ranging translocation, ring structure to deletion of the terminal band. 

Hemizygous deletion involving the 4p16.3 region of chromosome occurs spontaneously in approximately in 50 to 60% of the cases. Unbalanced translocation affects the rest [1]. Inversion or other structural rearrangements in the region are responsible for rare cases of WHS. 

The presentation and severity of this syndrome depend on the extent of the chromosomal deletion. Band 16.3 on chromosome 4p is an important region for the disorder and its deletion results in full expression of the disorder. Hence, it is also called as a critical region for the disorder. Mild cases occur with deletion of 3- 5 Mb. Classic symptoms of WHS occur when the deletion is between 5-18 Mb. More than 22Mb deletion is considered severe [2].

G-banded cytogenetic studies detects a deletion of band 4p14 in 50-60% of cases [3]. translocation leading to loss of part of chromosome 4 in the offsprings is seen in 20% of the cases [4] [5] [6].

Most of the documented cases of WHS involved sporadic genetic changes happened in very early stages of embryonic development. In the rest, balanced translocation in one of the parents determines the presentation.

An unbalanced translocation occurs when the broken pieces of two or more chromosomes do not properly fit into the recipient chromosome. Individuals with balanced translocation have a high risk of having children with unbalanced translocation. 

Epidemiology

WHS is a rare disorder which is misdiagnosed and hence, is underestimated. It is rare in occurrence with frequency ranging from 1 per 20,000 to 1 per 50,000 births [7] [8]. WHS shows high predominance in females with a ration of 2:1 [9] [10]. 

Sex distribution
Age distribution

Pathophysiology

The presentation of WHS depends on the extent of gene deletion. Genetic material present near the end of the short arm of chromosome 4 is lost and is written as 4p. The extent of this deletion varies among affected individuals. Larger the deletion, more severe is the physical anomalies and mental and psychological disability. WHS phenotypes are categorized into mild, moderate, and severe. Mild cases correlate with small deletions of less than 3.5 Mb and are mostly under-diagnosed. Presentation is mild without any major malformations.

The moderate form is the most frequent one with average deletions of 5-18 Mb. This is the most widely recognized form of WHS. Large deletions exceeding 22-25 Mb, cause severe phenotypic variations.

There is a critical region , WHSCR-2, in the terminal end of the short arm of chromosome 4 which when deleted leads to full expression of this syndrome. Genes commonly involved in patients with typical signs and symptoms includes WHSC1, LETM1,and MSX1.

Studies have found that the features such as development delay and distinctive characteristic features are associated with loss of WHSC1. Seizures or other abnormal activities in the brain are appeared to be associated with loss of LETM1 gene.

The oral and dental malformations such as cleft lip/palate are commonly seen with loss of the MSX1 gene.

Prevention

Genetic counselling and prenatal chromosomal analysis should be offered to families with one parent being a carrier involving the 16.3 band of the short arm of chromosome 4.

It helps in determining the genetic status in subsequent pregnancies.

Summary

Wolf-Hirschhorn syndrome is a constellation of abnormalities consisting of craniofacial aberrations, structural organ defects, mental and growth retardation, and seizures, all due to a partial deletion of the terminal band of the short arm of chromosome 4.

The severity of this syndrome is directly related to the extent of deletions and the presentation can be mild, moderate or severe. There is a critical region present in the chromosome which when deleted results in full expression of this syndrome. This region is called the wolf-Hirschhorn syndrome critical region (WHSCR). The characteristic features in WHS include abnormal nose, giving greek warrior helmet appearance, cranio-facial dysgenesis including hypertelorism, protruding eyes, prominent glabella, high-arched eyebrows, microcephaly and midline fusion defects.

Diagnosis can be made prenatally via conventional G-banded analysis, flourescence in situ hybridization, or chromosome microarray( CMA), which by far, is the most accurate diagnostic modality. Prenatal diagnosis can also be done by obstetric ultrasonography.

WHS requires a multidisciplinary treatment approach to deal with the respective abnormalities or symptoms. Genetic counselling is also vital for family members of the affected child.

Patient Information

Overview.

Wolf-Hirschhorn syndrome (WHS) is a genetic condition caused by loss of a part of chromosome 4. However, other defects in that part of the chromosome may also cause this condition. It is characterized by a number of abnormalities, particularly involving the face and bones.

Etiology/pathophysiology.

Chromosomes contain genes which carry genetic information. These genes are like codes for everything thing that has to do with an individual, from the appearance of the individual to the structure and functions of all organs in the body. There are 23 pairs of chromosomes in the body. In WHS, the fourth pair of chromosomes has a problem. A part of it is broken off and missing, thereby resulting in loss of the encoded genetic information. This results in abnormalities in structure and functions of different parts of the body.

Epidemiology.

This condition is estimated to occur in 1 of 20,000-50,000 births and it affects females more than males.

Presentation.

This condition is genetic and presents at birth. There are a lot of abnormalities associated with this syndrome, but the most frequently observed are the facial abnormalities, including a characteristic nose shape which consists of a very broad nasal bridge continuing with the forehead taking the shape of the greet warrior helmet. Other features include an abnormally small head, a deep hole in the middle of the upper lip and palate (cleft lip/palate), wide space between both eyes, fish-like mouth, small ears, and a very small jaw

A lot of abnormalities are observed in the bones of these patients, these include hip joint dislocations, abnormality of feet, two or more ribs fusing together, excessive bending of the spine. Virtually all organs in the body are affected, the heart can have several abnormalities, the urinary tract often presents with the urethra coming out, not at the tip of the penis, but behind and below the tip.

Very commonly, such children affected with WHS come down with delayed developmental milestones, such that they start walking, talking, writing much later in life than normal kids. Some might not get to reach these milestones at all. Mental retardation is a classic feature of WHS. The children would not be able to carry out social activities which are peculiar to their age group. 

Workup.

Chromosomal abnormalities are detected by a doctor using certain genetic tests. When a doctor sees a child with the facial features mentioned above, together with a delay in growth and mental development, WHS is suspected.

Treatment.

Since this syndrome affects almost every part of the body, it would take more than one specialist to treat this case. A heart surgeon, spine surgeon, eye specialist (ophthalmologist), orthopaedic surgeon, speech therapist, and a genetic counsellor would all work hand in hand to help manage the patient and the family members. However, the condition cannot be cured.

Prognosis.

Babies still in the womb may die before birth if they have this syndrome, those who survive at birth, may die within their first year of life. Serious mental and developmental disabilities are seen in those who survive beyond infancy.

References

Article

  1. Sheth F, Akinde OR, Datar C, Adeteye OV, Sheth J. Genotype-Phenotype
    Characterization of Wolf-Hirschhorn Syndrome Confirmed by FISH: Case Reports.
    Case Rep Genet. 2012;2012:878796. doi: 10.1155/2012/878796. Epub 2012 Nov 22.
  2. Zollino M, Murdolo M, Marangi G, Pecile V, Galasso C, Mazzanti L, Neri G. On
    the nosology and pathogenesis of Wolf-Hirschhorn syndrome: genotype-phenotype
    correlation analysis of 80 patients and literature review. Am J Med Genet C Semin
    Med Genet. 2008 Nov 15;148C(4):257-69.
  3. Wieczorek D. Wolf-Hirschhorn syndrome. Orphanet encyclopedia. 2003. Sep, [Last accessed on 2010 Oct 25].
  4. Bergemann AD, Cole F, Hirschhorn K. The etiology of Wolf-Hirschhorn syndrome.
    Trends Genet. 2005 Mar;21(3):188-95.
  5. Zollino M, Lecce R, Fischetto R, Murdolo M, Faravelli F, Selicorni A, Buttè C,
    Memo L, Capovilla G, Neri G. 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 Mar;72(3):590-7. Epub 2003 Jan 30.
  6. Zollino M, Lecce R, Selicorni A, Murdolo M, Mancuso I, Marangi G, Zampino G,
    Garavelli L, Ferrarini A, Rocchi M, Opitz JM, Neri G. A double cryptic chromosome
    imbalance is an important factor to explain phenotypic variability in
    Wolf-Hirschhorn syndrome. Eur J Hum Genet. 2004 Oct;12(10):797-804.
  7. Lurie IW, Lazjuk GI, Ussova YI, et al. The Wolf-Hirschhorn syndrome. I. Genetics. Clin Genet. 1980 Jun. 17(6):375-84.
  8. Maas NM, Van Buggenhout G, Hannes F, et al. Genotype-phenotype correlation in 21 patients with Wolf-Hirschhorn syndrome using high resolution array comparative genome hybridisation (CGH). J Med Genet. 2008 Feb. 45(2):71-80.
  9. 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 Oct;38(10):674-9.
  10. Coles K, Mackenzie M, Crolla J, Harvey J, Starr J, Howard F, Jacobs P. A complex rearrangement associated with sex reversal and the Wolf-Hirschhorn
    syndrome: a cytogenetic and molecular study. J Med Genet. 1992 Jun;29(6):400-6.
  11. Battaglia A, Filippi T, South ST, Carey JC. Spectrum of epilepsy and electroencephalogram patterns in Wolf-Hirschhorn syndrome: experience with 87 patients. Dev Med Child Neurol. 2009 May. 51(5):373-80. 

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Last updated: 2019-07-11 20:36