ceptable treatment.

The child was admitted to the

hospital within 1 hour and 40 minutes of arrival. A
previous admission for similar symptoms 10 months
before this ED visit resulted in a 3-hour, 20-minute
ED visit. At that time, an alternate care plan had been
established but the EOAD document system had not
been implemented, necessitating extensive discussions with the parents, primary care physicians, and
hospice personnel.
Although parental satisfaction with the EOAD
program has not been rigorously assessed, current
informal feedback indicates a high level of satisfaction and a sense of relief that parents do not need to
be physically present with their children 24 hours a
day to implement an alternative plan of care.
CONCLUSIONS

In summary, pediatric advance directives present

complex issues for physicians, especially in the absence of an affirming parent. Issues of directive interpretation, parental choice, and legal risk were addressed by the development of a standard document
that limits treatment options and identifies parental
responsibilities for revision or revocation. The document also contains a parental agreement to hold the
health care providers harmless from liability. Use of
the document requires education, a tracking system,
and yearly completion of a new advance directive
form.
Christine M. Walsh-Kelly, MD*
Kellie R. Lang, RN, JD
Jane Chevako, MD
Ellen L. Blank, MD
Nancy Korom, RN, MSN
Kristi Kirk, RN
Amanda Gray, RN, BSN, RTS
*Emergency Department
Childrens Hospital of Wisconsin
Milwaukee, WI 53226
REFERENCES
1. Cox DM, Sachs GA. Advance directives and the patient selfdetermination act. Clin Geriatr Med. 1994;10:431 443
2. Hoffmann DE, Zimmerman SI, Tompkins CJ. The dangers of directives
or the false security of forms. J Law Med Ethics. 1996;24:517
3. Smith G. New EMS palliative care/DNR protocol will replace existing
hospice protocol (Practice Issues). Md Med J. 1995;44:717722
4. Iserson KV. A simplified prehospital advance directive law: Arizonas
approach. Ann Emerg Med. 1993;22:60 67
5. Guidelines for Do Not Resuscitate orders in the prehospital setting
(Position Paper). Ann Emerg Med. 1988;17:169 171
6. Natural death declaration to physicians and do-not-resuscitate orders.
State of Wisconsin Act 200 of 1995 (Assembly Bill 658); Date of
enactment: April 4, 1996; Date of publication: April 17, 1996
7. Levetown M, Pollack MM, Cuerdon TT, Ruttimann UE, Glover JJ.
Limitations and withdrawals of medical intervention in pediatric critical care. JAMA. 1994;272:12711275
8. Yellin PB, Fleischman AR. DNR in the DR?. J Perinatol. 1995;15:232236
9. Harrison H. Need exists for advance directives from parents. J Perinatol.
1995;15:522. Letter
10. Alecson DG. Need exists for advance directives from parents. J Perinatol.
1995;15:520 522. Letter; Comment
11. Sahler OJ, Greenlaw J. Pediatrics and the Patient Self-Determination
Act. Pediatrics. 1992;90:999 1001

830

EXPERIENCE AND REASON

Natural History of WolfHirschhorn Syndrome: Experience

With 15 Cases
ABSTRACT. Wolf-Hirschhorn syndrome (WHS) is a
well-known chromosomal disorder attributable to partial
deletion of the short arm of chromosome 4 (4p-). Although about 120 cases have been reported so far, there is
still very little data on its natural history. Information
given to parents at the time of diagnosis tends to be
skewed to the extreme negative. To help delineate more
thoroughly the natural history of WHS, and to obtain
better information to answer parents questions in a clinical setting, we evaluated 15 patients (12 females, 3
males) in three centers with the 4p- syndrome. Four of the
cases had a follow-up spanning 16 years. Thirteen cases
were detected by standard cytogenetics (regular G-banding 10, high-resolution banding 3), while the remaining 2
required fluorescence in situ hybridization. A total of
5/15 (33.3%) had heart lesions; 7/15 (46.6%) had oral facial
clefts; 13/15 (86.6%) had a seizure disorder, that tended to
disappear with age; and 100% had severe/profound developmental retardation. One Italian patient had sensorineural deafness and 1 Utah patient had a right split
hand defect. Of note, 2 Utah patients were able to walk
with support (at 4 and 12 years of age, respectively),
whereas 3 Italian patients and 1 Utah patient were able to
walk unassisted (at 4, 5, 5 years 9 months, and 7 years of
age, respectively). Two of the 3 Italian patients also
achieved sphincter control (by day). The 8 patients receiving serial electroencephalogram studies showed
fairly distinctive abnormalities, usually outlasting seizures. A slow, but constant progress in development was
observed in all cases, during the follow-up period. In
conclusion, the combined cases of the three centers represent considerable experience, providing new information on several aspects of this important deletion
syndrome. Pediatrics 1999;103:830 836; Wolf-Hirschhorn
syndrome; del(4p) syndrome; natural history.
ABBREVIATIONS. WHS, Wolf-Hirschhorn syndrome; FISH, fluorescence in situ hybridization; EEG, electroencephalogram; MRI,
magnetic resonance imaging; CT, computed tomography.

olf-Hirshhorn syndrome (WHS) is a wellknown chromosomal disorder first described by Cooper and Hirschhorn in 1961.1
It is attributable to partial loss of material from the
short arm of chromosome 4, with the majority of
cases (87%) being de novo deletions,2 of preferential
paternal origin.3,4 Only in 1965, however, was this
disorder brought to the attention of geneticists.5,6
Since then numerous additional cases have been
published.714 Despite these clinical articles, however,
there are still very little data on the natural history of
WHS. There also tends to be a skewing of information to the extreme negative, with families usually
Received for publication Mar 12, 1998; accepted Sep 11, 1998.
Address correspondence and reprint requests to Agatino Battaglia, MD,
Stella Maris Scientific Research Institute, Institute of Child Neurology and
Psychiatry, University of Pisa, via dei Giacinti, 256018 Calambrone, Pisa,
Italy.
PEDIATRICS (ISSN 0031 4005). Copyright 1999 by the American Academy of Pediatrics.

Downloaded from by guest on May 18, 2016

being told that their child has very little chance, if

any, for meaningful interaction with his or her relatives and peers; that he will never walk or achieve
sphincter control; and that he will have a serious
seizure disorder.
The purpose of this article is to help delineate
more thoroughly the natural history of WHS, and to
obtain better information to answer parents questions in a clinical setting.
Accurate information is of paramount importance
to obstetricians and pediatricians who assist families
in making relevant decisions about possible interruption of pregnancy, who help the family adjust to
the birth of a baby with monosomy 4p, and who, in
several cases, provide health care for many years15,16.
GENERAL CLINICAL DATA

We have evaluated 15 patients in three centers

with the 4p- syndrome. Eleven of these patients are
described for the first time. Four (cases 1, 2, 3, and 7)
were reported previously17,18; 2 of them (cases 3 and
7) showed novel, as yet unreported, clinical findings,
such as sensorineural hearing deafness and right
split hand.
There were 12 females and 3 males. Age at first
observation ranged between newborn and 9 years.
Eight of the cases, five from Italy and three from
Utah, have been followed from 512 years to 16 years.
Thirteen cases were detected by standard cytogenetics, either by regular G-banding (cases 1, 5, 7, 9,
10, 11, 12, 13, 14, and 15) or high-resolution banding
(cases 4, 6, 8), whereas the remaining 2 Italian cases
(cases 2 and 3) required fluorescence in situ hybridization (FISH) analyses. In fact, they had been observed previously in different university hospitals
and the diagnosis had been missed, because standard cytogenetics studies were negative.
On the other hand, 6 of the Utah cases, (4, 5, 6, 7,
9, and 11), excluding the 4 oldest, were confirmed
using FISH probes in the critical Wolf-Hirschhorn
region.
All patients were born at term and were small for
gestational age. Parental ages were similar to the
general population. Pregnancy and family history
were generally unremarkable. Birth history was noncontributory for all but 4 cases, (1, 2, 3, and 15), in
whom some degree of perinatal distress was present.

and 1 Italian patient (case 15) underwent gastrostomy.

Congenital heart lesions, in the form of patent
ductus arteriosus associated with ventricular septal
defect (case 7) or aortic insufficiency (case 13), isolated atrial septal defect (cases 5 and 12) and pulmonary stenosis (case 15) were found in 5 patients.
Bladder exstrophy and obstructive uropathy were
observed in only 1 patient (case 13), while chronic
urinary tract infections secondary to vesicoureteral
reflux were reported in another (case 12).
Four Utah patients (cases 4, 6, 10, and 13) showed
conduction hearing defects, attributable to very frequent otitis media, whereas bilateral sensorineural
hearing loss was diagnosed in 1 Italian patient (case
3) at 15 months of age.
A variety of skeletal anomalies were found in
66.6% of the patients. Those consisted of right split
hand (case 7) (Fig 4), clinodactyly (cases 1, 3, and 12),
club feet (cases 8 and 10), scoliosis and kyphosis
(cases 10 and 13), malformed toes (case 3), finger-like
appearance of the thumb, and thin fingers with bilateral overriding of the second finger onto the third
(case 10).
In the 5 Italian patients (cases 1, 2, 3, 14, and 15)
with skeletal radiograph examinations, a severely
delayed bone age was found, together with a number
of anomalies, such as craniostenosis with brachycephalic skull, small iliac alae with coxa valga subluxans (case 2), double first phalanx of the first ray of
the left foot and absence of the ossification nucleus
for the ulnar styloid apophysis (case 3), and lack of
pubic bone ossification (case 15).
Abnormal tooth development was present in the 4
Italian patients checked for it. There were agenesis of
the lower lateral incisors and of the right upper
canine (case 1); delayed tooth eruption with persistence of deciduous teeth at 9 years (cases 2 and 15);
and peg-shaped teeth (case 3).
Skin changes were observed in most patients, and
were characterized by cutis marmorata, dry skin, or
hemangioma. Sacral dimples and tuft of hair on the
back were also observed.
One of the 2 oldest patients (case 3, age 16 years)
had her menarche at 12 years 7 months, with regular
menses.

CLINICAL FINDINGS

NEUROLOGIC FINDINGS

The clinical findings of our patients are listed in

Table 1.
All of them showed a characteristic craniofacial
appearance with microcephaly, some degree of skull
asymmetry, the Greek warrior helmet appearance
of the nose, hypertelorism, highly arched eyebrows,
distinct mouth with downturned corners (Fig 1), simple or posteriorly angulated ears, preauricular skin
tags or pits (Fig 2), bilateral cleft lip and palate (Fig 3)
or cleft palate, short philtral length and micrognathia.
All patients showed short stature and slow weight
gain (less than third centile), despite adequate caloric
and protein intake. In view of severe feeding difficulties, 6 Utah patients (cases 4, 6, 9, 11, 12, and 13)

Thirteen of our patients had seizures, starting between 5 to 23 months of age, with an obvious peak
incidence at around 9 to 10 months. Seizures were
either unilateral clonic, with or without secondary
generalization, or generalized tonic clonic from the
beginning; they were mostly facilitated by fever, on
occasions lasting .15 minutes, and often occurred in
clusters.
Unilateral or generalized, prolonged clonic or tonic-clonic status epilepticus occurred in 6 patients
(cases 4, 7, 8, 11, 13, and 15) on several occasions,
despite adequate antiepileptic treatment.
In addition, atypical absences, occasionally accompanied by a mild myoclonic component, were observed in 9 patients (cases 1, 3, 4, 6, 11, 12, 13, 14, and

Downloaded from by guest on May 18, 2016

EXPERIENCE AND REASON

831

832
EXPERIENCE AND REASON

TABLE 1. Clinical Findings in 15 Patients With Wolf-Hirschhorn Syndrome

Case 1
Age at the Last
Examination

Downloaded from by guest on May 18, 2016

Sex
Intrauterine growth retardation
Decreased fetal
movements
Microcephaly
Skull asymmetry
Greek warrior helmet
Hypertelorism
Highly arched
eyebrows
Iris/optic nerve defect
Distinct mouth
Simple, angulated
ears
Cleft lip/palate
Short philtrum
Micrognathia
Heart defect
Hearing loss
Skeletal anomalies
Skin changes
Seizures
Hypotonia
Muscle hypotrophy
Ambulation
Sphincter control
Stereotypies

Case 2

Case 3

Case 4

Case 5

Case 6

Case 7

Case 8

Case 9

Case 10

Case 11

Case 12

Case 13

Case 14 Case 15

9 Years 12 Years 16 Years 4 Years

1 Year
3 Years
1 Year 9 Years 6 Months 16 Years 2 Years 11 Years 8 Years 7 Years 9 Years % Clinical
6 Months
9 Months 9 Months 5 Months 5 Months
10 Months
6 Months 6 Months
Features
F
1
1

F
1
1

F
1
1

F
1
2

F
1
1

M
1
1

F
1
1

F
1
1

M
1
1

F
1
1

F
1
1

F
1
1

F
1
1

F
1
1

M
1
1

100%
93.3%

1
1
1
1
1

1
2
1
1
1

1
1
1
1
1

1
1
1
1
1

1
2
1
1
1

1
2
1
1
1

1
2
1
1
1

1
1
1
1
1

1
1
1
1
1

1
1
1
1
1

1
1
1
1
1

1
2
1
1
1

1
1
1
1
1

1
2
1
1
1

1
2
1
1
1

100%
53.3%
100%
100%
100%

1
1
1

2
1
1

2
1
2

2
1
1

2
1
1

2
1
1

2
1
1

2
1
1

1
1
1

1
1
1

1
1
1

2
1
1

2
1
1

2
1
1

1
1
1

33.3%
100%
93.3%

2
1
1
2
2
1
1
1
1
1
1
1
1

2
1
1
2
2
2
1
1
1
1
2
2
1

2
1
1
2
1
1
1
1
1
1
1
1
1

1
1
1
2
1
1
1
1
1
1
1
2
1

1
1
1
1
2
2
1
2
1
1
2
2
1

1
1
1
2
1
2
2
1
1
1
2
2
1

2
1
1
1
2
1
2
1
1
1
2
2
1

2
1
1
2
2
1
1
1
1
1
2
2
1

1
1
1
2
2

1
1
1
2
1
1
1
1
2
1
1
2
1

1
1
1
2
2
1
1
1
1
1
2
2
1

2
1
1
1
2
1
2
1
1
1
1
2
2

2
1
1
1
1
1
2
1
1
1
2
2
1

2
1
1
2
2
2
1
1
1
1
1
2
2

1
1
1
1
2
1
1
1
1
1
2
2
1

46.6%
100%
100%
33.3%
33.3%
66.6%
66.6%
86.6%
93.3%
93.3%
40.0%
13.3%
80.0%

2
2
1
2
2
2
2

Fig 1. Case 5, at 1 year 9 months of age, showing the typical

Greek warrior helmet appearance of the nose, hypertelorism,
highly arched eyebrows, repaired cleft lip, distinct mouth with
downturned corners.

15), by 1 to 5 years of age. These were well-controlled

by the usual antiepileptic drugs.
In the 7 older patients (cases 1, 2, 3, 8, 10, 12, and
15, ranging in age from 9 to 16 years) seizures had
stopped by 3 to 8 years of age, and 3 of them have
been off medication for a few years.
Eight of our patients (cases 1, 2, 3, 4, 10, 12, 14, and
15), who received serial electroencephalographic
(EEG) studies over time, showed fairly distinctive
abnormalities. These included: frequent, ill-defined,
high-amplitude, sharp element-spike/wave complexes at 2-to 3.5-Hz, usually diffuse, occurring in
long bursts, and activated by slow wave sleep; and
frequent high-amplitude, spikes, polispikes/wave
complexes at 4- to 6-Hz, over the posterior third of
the head, often only seen with the eyes closed.19 Such
paroxysms were accompanied by recognizable clini-

Fig 2. Case 5, at 7 weeks of age, showing preauricular skin tags

and posteriorly angulated left ear.

Fig 3. Case 5, at 7 weeks of age, showing bilateral cleft lip.

cal changes (atypical absences) in a minority of patients, only in early years, and could be observed for
many years even after seizures had stopped.
Brain magnetic resonance imaging (MRI) studies
were conducted on 6 patients. In 3 (cases 1, 2, and 3)
there were multifocal white matter hyperintensity
areas in T2-weighted images, probably related to the
perinatal distress; in 2 patients (cases 4 and 14) there
was thinning of the corpus callosum, associated, in
case 4, with diffusely decreased volume of the white
matter, and in 1 patient (case 15) corpus callosum
agenesis was observed. Computed tomography (CT)

Fig 4. Case 7, at 1 year 5 months of age, showing right split hand.

Downloaded from by guest on May 18, 2016

EXPERIENCE AND REASON

833

of the brain was performed in 2 patients (cases 7 and

11) and, while showing enlargement of the lateral
and third ventricles with areas of periventricular
cystic change anteriorly in case 7, was normal in case
11.
Hypotonia and muscle hypotrophy, particularly of
the lower limbs, were observed in almost all patients.
Stereotypies, such as holding the hands in front of
the face, hand-washing or flapping, patting self on
chest, rocking, head-shaking, and stretching of legs
were observed in 12 patients (Fig 5).
DEVELOPMENTAL FINDINGS

All but the youngest patient, who is currently 6

months old, had severe to profound developmental delay and mental retardation, with absence of
speech, which, in the older cases, was limited to
babbling or guttural sounds, occasionally modulated in a communicative way. Comprehension
was limited to simple orders or to a specific context.
An intention to communicate appeared to be
present, to some extent, in 9 patients, but was poor or
absent, in the early years, in 5. In particular the latter
did not smile in response to seeing their mother, did
not look at her while being breastfed, did not follow
with their eyes, and often reacted by crying to both
the human face and voice. As discussed below, this
disorder of affect tended to improve over time.
Two children from Utah (cases 4 and 10) walked
with support by age 4 and 12 years, respectively. The
oldest child (case 10) is also a self-feeder, and helps
in dressing and undressing herself, but has no
graphic abilities.
Three patients from Italy (cases 1, 3, and 14) and
1 more Utah patient (case 12) walked alone at ages
5 years 9 months, 4 years, 5 years, and 7 years,

Fig 5. Case 8, at 8 years 9 months of age, showing hand-washing

stereotypies.

834

EXPERIENCE AND REASON

respectively. Presently, at age 912, 16, 712, and 11

years, respectively, all walk with a broad-based
gait and with poor swinging movements of the
upper limbs. Two of the 3 Italian patients (cases 1
and 3) achieved sphincter control, only during the
day, at ages 8 years 9 months and 14 years, respectively. Their graphic abilities were limited to scribbling, and they occasionally helped to set and clear
the dinner table, bring a spoon with some food to
their mouths, and dress and undress themselves.
The follow-up of our patients, spanning 16 years,
showed that the disorder of affect, observed in 5 of
them, tended to improve over time, as did the motor
abilities.
On the whole there has been an evolution from the
affective point of view, with improved abilities of
adaptation to new situations and an initial differentiation of the I processes. An improvement in the
communicative abilities and verbal comprehension
with extension of the gesture repertoire and a decrease occurrence of withdrawal and anxiety behaviors was also observed.
DISCUSSION

Children with WHS often do face serious physical disabilities, such as failure to thrive, respiratory problems, club feet, and hard-to-control seizures. Both doctors and parents have, then, to deal
with difficult decisions regarding the care of the
child.
Why operate to correct club feet on a child who
will never learn to walk?, Should we operate to
correct a severe kyphosis-scoliosis in a child with
severe mental retardation?: these are only some of
the complex questions facing both doctors and families.20 It is, therefore, of the utmost importance that
up-to-date information be available in the literature.
This can prove to be an invaluable resource to medical professionals and families.
Our experience with the natural history of WHS
expands literature reports, particularly on some issues.
All patients have the characteristic facial phenotype, which, while slightly changing over time,
remains easy to recognize into adolescence (Fig 6).
One of the major concerns for parents of children
with 4p- and for professionals involved in their
care is the occurrence of seizures. They are observed in 50% to 100% of cases.9,10,12,13 Although
initially difficult to control in some of them, they
eventually tend to disappear with age, as shown in
our patients.
In the medical literature very little is known about
the EEG findings in WHS.8,21 Our data show that
patients with WHS have fairly distinctive EEG features, outlasting seizures, and not necessarily related
to them.19 We feel that this observation could be
highly relevant to improve medical treatment of such
patients, who, on some occasions (case 10), despite
having been seizure-free for quite a long time, are
still given antiepileptic drugs, because of such striking EEG abnormalities.
The brain MRI/CT findings observed in our cases
4, 14, 15, and 7 seem to extend the scant neuropatho-

Downloaded from by guest on May 18, 2016

Fig 6. Frontal views at different ages

of some of our patients, from infancy
(A, at 3 months of age; B, at 5 months
of age), through childhood (C, at 1 year
4 months of age; D, at 1 year 9 months
of age; E, at 2 years 10 months of age; F,
at 3 years of age; G, at 3 years 8 months
of age; H, at 6 years of age; I, at 9 years
of age, J, at 9 years of age), to adolescence (K, at 12 years of age; L, at 14
years of age; M, at 16 years of age). A
through M, starting from upper left,
looking from left to right. Figures 6G,
6I, and 6L were reproduced with permission from the following article: Battaglia A. Riv Ital Pediatr (IJP). 1997;23:
254 259.

logic data available in literature on 4p- syndrome.2224

Therefore, we would suggest serious consideration
of neuroimaging studies in all such patients, to
deepen our knowledge on the underlying brain pathology.
In addition to seizures the other most consistent
medical problem of infancy is major feeding difficulty. Six of the Utah patients required gastrostomy
in infancy to protect the airway, while 1 Italian patient received gastrostomy only at 4 years 8 months
of age (weight, 6800 g) with a consequent considerable improvement in weight gain and motor abilities.
Gastroesophageal reflux is also common. We would
suggest that infants with 4p- who have feeding difficulties receive swallow studies and early consideration for gastrostomy tube use.
Although in the past there have been some attempts at relating the size of the chromosomal deletion to the clinical features, it is now clear that variations in deletions of the short arm of chromosome 4
do not result in detectable differences in the phenotype.2527 It seems, then, even more interesting to note
that 4 of our patients (cases 1, 3, 12, and 14), who
achieved somewhat advanced developmental milestones compared with other cases, were detected by
regular G-banding (cases 1, 12, and 14) and FISH
analysis (case 3), respectively.
This, again, suggests that it is not necessarily the
smaller deletion that accounts for a less severe outcome. Such a lack of correlation between clinical
severity and size of the deleted segment might reflect
the actual number and/or the specific function of
genes in the additionally deleted region. It is of note
that molecular genetic studies have delineated a
WHS critical region of approximately 165 kbp in the
4p16.3 band.27
Other, as yet unreported abnormalities, such as

bilateral sensorineural deafness and right split hand,

respectively observed in our cases 3 and 7, seem to be
component manifestations of WHS. It might then be
advisable to carry out a proper audiologic examination of such patients, to rule out a possible hearing
impairment, which, if not recognized, might worsen
the childs prognosis.
We followed some of our patients up to 16 years,
and could observe a clear improvement over time of
both the disorder of affect and the motor abilities.
Although it is clear that persons with WHS have
a severe or profound degree of mental retardation,
it is evident to us that there is more acquisition of
milestones than suggested by the medical literature.28 In fact, contrary to what conventionally
stated, 6 of our patients were able to walk either
alone (cases 1, 3, 12, and 14) or with support (cases
4 and 10); 3 of them (cases 1, 3, and 10) were
capable of performing simple household tasks,
feeding, dressing, and undressing themselves to
some extent; and 2 of them (cases 1 and 3) became
toilet trained by day.
Our series consists of 12 females and 3 males. This
female predominance of cases has been noted in the
literature.29 In recent years guidelines for routine
health supervision in the primary care setting have
been proposed for children with various syndromes.30 From this context we would suggest the
following for routine care of infants and children
with 4p-:
Infancy-focused examination of the heart; ophthamology consultation; audiologic screening; developmental testing/referral for early intervention; renal ultrasound; swallowing study (if any
feeding difficulties); EEG (if seizures).

Downloaded from by guest on May 18, 2016

EXPERIENCE AND REASON

835

 Childhood-continued developmental testing/

appropriate school placement; follow-up EEG (if
seizures).
Participation in support groups is an important
strategy for many parents in the coping with a child
with disabilities.31 The parents of the Utah cases
banded together to form a local parent support
group. There are two existing support organizations
in North America for families of children with 4p-:
The Wolf-Hirshhorn Syndrome Network and the
Support Organization for Trisomy 18,13, and Related
Disorders (SOFT). These groups can be contacted
through the Internet.
Although WHS is widely considered to be a deletion
syndrome,32 we believe that there might be quite a
number of yet unrecognized and misdiagnosed cases
in which there is a microdeletion, not shown on standard cytogenetics. We wish to stress the serious difficulty encountered in confirming the provisional clinical
diagnosis in such patients (see our cases 2 and 3) and to
alert clinicians and make them cognizant of the need to
pursue high-resolution banding and molecular analyses (FISH) in suspect WHS cases. We think that the
condition is less rare than actually thought.
Agatino Battaglia, MD*
John C. Carey, MD
Peeches Cederholm, BS
David H. Viskochil, MD, PhD
Arthur R. Brothman, PhD
Cinzia Galasso, MD
*Stella Maris Scientific Research Institute
Institute of Child Neurology and Psychiatry
University of Pisa
256018 Calambrone, Pisa, Italy
Division of Medical Genetics
Department of Pediatrics
University of Utah Health Sciences Center
Salt Lake City, UT 84132
Institute of Pediatrics
University of Rome
S Eugenio Hospital
Rome, Italy 00100
ACKNOWLEDGMENTS
This work was supported in part by the International Program
for Consultation and Research in Clinical Genetics of the University of Utah.
We thank the families of the children with WHS who kindly
participated in our project.

REFERENCES
1. Cooper H, Hirschhorn K. Apparent deletion of short arms of one
chromosome (4 or 5) in a child with defects of midline fusion. Mamm
Chrom Nwsl. 1961;4:14
2. Lurie IW, Lazjuk GL, Ussova I, Presman EB, Gurevich DB. The WolfHirschhorn syndrome. I. Genetics. Clin Genet. 1980;17:375384
3. Tupler R, Bortotto L, Buhler EM, et al. Paternal origin of the de novo
deleted chromosome 4 in Wolf-Hirschhorn syndrome. J Med Genet.
1992;29:5355
4. Dallapiccola B, Mandich P, Bellone E, et al. Parental origin of chromosome 4p deletion in Wolf-Hirschhorn syndrome. Am J Med Genet. 1993;
47:921924
5. Wolf U, Reinwein H, Porsh R, Schroter R, Baitsch. Defizienz am den
kurze Armen eines chromosomes nr. 4. Humangenetik. 1965;1:
397 413

836

EXPERIENCE AND REASON

6. Hirschhorn K, Cooper H, Firschein IL. Deletion of short arms of chromosome 4 5 in a child with defects of midline fusion. Humangenetik.
1965;1:479 482
7. Arias D, Passarge E, Engle MA, German J. Human chromosomal
deletion: two patients with the 4p- syndrome. J Pediatr. 1970;76:
82 88
8. Miller OJ, Breg WR, Warburton D, et al. Partial deletion of the short arm
of chromosome n 4(4p-): clinical studies in five unrelated patients.
J Pediatr. 1970;77:792 801
9. Guthrie RD, Aase JM, Asper AC, Smith D. The 4p- syndrome. Am J Dis
Child. 1971;122:421 425
10. Centerwall WR, Thompson WP, Allen IE, Fobes CD. Translocation 4psyndrome. Am J Dis Child. 1975;129:366 370
11. Wilcox LM, Bercovitch L. Ophthalmic features of chromosome deletion
4p- (Wolf-Hirschhorn). Am J Ophthalmol. 1978;86:834 839
12. De Grouchy J, Turleau C. Clinical Atlas of Human Chromosomes. 2nd ed.
New York, NY: John Wiley; 1984
13. Stengel-Rutkowski S, Warkotsch A, Schimanek P, Stene J. Familial
Wolfs syndrome with a hidden 4p deletion by translocation of an 8p
segment. Unbalanced inheritance from a maternal translocation
(4;8)(p15.3;p22). Case report, review and risk estimates. Clin Genet.
1984;25:500 521
14. Reid I, Morrison N, Barron L, et al. Familial Wolf-Hirschhorn syndrome
resulting from a cryptic translocation: a clinical and molecular study.
J Med Genet. 1996;33:197202
15. Opitz JM. Twenty-seven-year follow-up in the Wolf-Hirschhorn syndrome. Am J Med Genet. 1995;55:459 461
16. Wheeler PG, Weaver DD, Palmer CG. Familial translocation resulting in
Wolf-Hirschhorn syndrome in two related unbalanced individuals: clinical evaluation of a 39-year-old man with Wolf-Hirschhorn syndrome.
Am J Med Genet. 1995;55:462 465
17. Battaglia A. Sindrome di Wolf-Hirschhorn(4p-): una causa di ritardo
mentale grave di difficile diagnosi. Riv Ital Pediatr (IJP). 1997;23:
254 259
18. Bamshad M, OQuinn JR, Carey JC. Brief clinical report: WolfHirschhorn syndrome and a split hand malformation. Am J Med Genet.
1998;75:351354
19. Battaglia A, Carey JC, Thompson JA, Filloux FM. EEG studies in the
Wolf-Hirschhorn(4p-) syndrome. EEG Clin Neurophysiol. 1996;99(4):
324
20. Schaefer BG, Kleimola CN, Stenson C, Daley SE, Farmer P, Holladay K.
Wolf-Hirschhorn Syndrome (Deletion 4p): A Guidebook for Families. Omaha,
NE: SOFT 18, 13 and RD and Meyer Rehabilitation Institute, University
of Nebraska Medical Center; 1996
21. Sgro` V, Riva E, Canevini MP, et al. 4p- syndrome: a chromosomal
disorder associated with a particular EEG pattern. Epilepsia. 1995;36:
1206 1214
22. Lazjuk GL, Lurie IW, Ostrowskaja TI, et al. The Wolf-Hirschhorn syndrome. II. Pathologic anatomy. Clin Genet. 1980;18:6 12
23. Gonzales CH, Capelozzi VL, Wajntal A. Brief clinical report: pathologic
findings in the Wolf-Hirschhorn (4p-) syndrome. Am J Med Genet.
1981;9:183187
24. Gottfried M, Lavine L, Roessmann U. Neuropathological findings in
Wolf-Hirschhorn(4p-) syndrome. Acta Neuropathol. 1981;55:163165
25. Wilson MG, Towner JW, Coffin GS, Ebbin AJ, Siris E, Brager P. Genetic
and clinical studies in 13 patients with the Wolf-Hirschhorn syndrome
[del(4p)]. Hum Genet. 1981;59:297307
26. Estabrooks LL, Lamb AN, Aylsworth AS, Callanan NP, Rao KW. Molecular characterization of chromosome 4p deletions resulting in WolfHirschhorn syndrome. J Med Genet. 1994;31:103107
27. Wright TJ, Ricke DO, Denison K, et al. A transcript map of the newly
defined 165 kb Wolf-Hirschhorn syndrome critical region. Hum Mol
Genet. 1997;6:317324
28. Guthrie RD, Aase JM, Asper AC, Smith DW. The 4p- syndrome. A
clinically recognizable chromosomal deletion syndrome. Am J Dis Child.
1971;122:421 425
29. Gorlin RJ, Cohen MM, Levin LS. Syndromes of the Head and Neck. New
York, NY: and Oxford, England: Oxford University Press; 1990:
46 48
30. Carey JC. Health supervision and anticipatory guidance for children
with genetic disorders (including specific recommendations for Trisomy 21, Trisomy 18, and Neurofibromatosis I). Pediatr Clin North Am.
1992;39:2553
31. Black RB, Weiss JC. A professional partnership with genetic support
groups. Am J Med Genet. 1988;29:2133
32. Jorde LB, Carey JC, White RL. Medical Genetics. St Louis, MO: MosbyYear Book Inc; 1995:120 121

Downloaded from by guest on May 18, 2016

Natural History of Wolf-Hirschhorn Syndrome: Experience With 15 Cases

Agatino Battaglia, John C. Carey, Peeches Cederholm, David H. Viskochil, Arthur R.
Brothman and Cinzia Galasso
Pediatrics 1999;103;830
Updated Information &
Services

including high resolution figures, can be found at:

/content/103/4/830.full.html

References

This article cites 28 articles, 4 of which can be accessed free

at:
/content/103/4/830.full.html#ref-list-1

Citations

This article has been cited by 6 HighWire-hosted articles:

/content/103/4/830.full.html#related-urls

Subspecialty Collections

This article, along with others on similar topics, appears in the

following collection(s):
Fetus/Newborn Infant
/cgi/collection/fetus:newborn_infant_sub
Genetics
/cgi/collection/genetics_sub

Permissions & Licensing

Information about reproducing this article in parts (figures,

tables) or in its entirety can be found online at:
/site/misc/Permissions.xhtml

Reprints

Information about ordering reprints can be found online:

/site/misc/reprints.xhtml

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright 1999 by the American Academy of Pediatrics. All rights
reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on May 18, 2016

Natural History of Wolf-Hirschhorn Syndrome: Experience With 15 Cases

Agatino Battaglia, John C. Carey, Peeches Cederholm, David H. Viskochil, Arthur R.
Brothman and Cinzia Galasso
Pediatrics 1999;103;830

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/103/4/830.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1999 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from by guest on May 18, 2016