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ceptable treatment. The child was admitted to thehospital within 1 hour and 40 minutes of arrival. Aprevious admission for similar symptoms 10 months

before this ED visit resulted in a 3-hour, 20-minuteED visit. At that time, an alternate care plan had beenestablished but the EOAD document system had not

been implemented, necessitating extensive discus-sions with the parents, primary care physicians, andhospice personnel.

Although parental satisfaction with the EOAD

program has not been rigorously assessed, currentinformal feedback indicates a high level of satisfac-tion and a sense of relief that parents do not need to

be physically present with their children 24 hours aday to implement an alternative plan of care.

CONCLUSIONS

In summary, pediatric advance directives presentcomplex issues for physicians, especially in the ab-sence of an affirming parent. Issues of directive in-terpretation, parental choice, and legal risk were ad-dressed by the development of a standard document

that limits treatment options and identifies parentalresponsibilities for revision or revocation. The docu-ment also contains a parental agreement to hold thehealth care providers harmless from liability. Use ofthe document requires education, a tracking system,and yearly completion of a new advance directiveform.

Christine M. Walsh-Kelly, MD*Kellie R. Lang, RN, JDJane Chevako, MDEllen L. Blank, MDNancy Korom, RN, MSNKristi Kirk, RNAmanda Gray, RN, BSN, RTS*Emergency DepartmentChildrens Hospital of WisconsinMilwaukee, WI 53226

REFERENCES

1. Cox DM, Sachs GA. Advance directives and the patient self-

determination act. Clin Geriatr Med. 1994;10:431443

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;22:60675. Guidelines for Do Not Resuscitate orders in the prehospital setting

(Position Paper). Ann Emerg Med. 1988;17:169171

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 criti-

cal 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;15:520522. Letter; Comment

11. Sahler OJ, Greenlaw J. Pediatrics and the Patient Self-Determination

Act.Pediatrics. 1992;90:9991001

Natural History of Wolf-Hirschhorn Syndrome: ExperienceWith 15 Cases

ABSTRACT. Wolf-Hirschhorn syndrome (WHS) is awell-known chromosomal disorder attributable to partialdeletion of the short arm of chromosome 4 (4p-). Al-though about 120 cases have been reported so far, there isstill very little data on its natural history. Information

given to parents at the time of diagnosis tends to beskewed to the extreme negative. To help delineate morethoroughly the natural history of WHS, and to obtainbetter information to answer parents questions in a clin-ical setting, we evaluated 15 patients (12 females, 3males) in three centers with the 4p- syndrome. Four of thecases had a follow-up spanning 16 years. Thirteen caseswere detected by standard cytogenetics (regular G-band-ing 10, high-resolution banding 3), while the remaining 2required fluorescence in situ hybridization. A total of5/15 (33.3%) had heart lesions; 7/15 (46.6%) had oral facialclefts; 13/15 (86.6%) had a seizure disorder, that tended todisappear with age; and 100% had severe/profound de-velopmental retardation. One Italian patient had senso-rineural deafness and 1 Utah patient had a right splithand defect. Of note, 2 Utah patients were able to walkwith support (at 4 and 12 years of age, respectively),whereas 3 Italian patients and 1 Utah patient were able towalk unassisted (at 4, 5, 5 years 9 months, and 7 years ofage, respectively). Two of the 3 Italian patients alsoachieved sphincter control (by day). The 8 patients re-ceiving serial electroencephalogram studies showedfairly distinctive abnormalities, usually outlasting sei-zures. A slow, but constant progress in development wasobserved in all cases, during the follow-up period. Inconclusion, the combined cases of the three centers rep-resent considerable experience, providing new informa-tion on several aspects of this important deletionsyndrome.Pediatrics 1999;103:830 836;Wolf-Hirschhorn

syndrome; del(4p) syndrome; natural history.

ABBREVIATIONS. WHS, Wolf-Hirschhorn syndrome; FISH, flu-orescence in situ hybridization; EEG, electroencephalogram; MRI,magnetic resonance imaging; CT, computed tomography.

Wolf-Hirshhorn syndrome (WHS) is a well-known chromosomal disorder first de-scribed by Cooper and Hirschhorn in 1961.1

It is attributable to partial loss of material from theshort arm of chromosome 4, with the majority ofcases (87%) being de novo deletions,2 of preferentialpaternal origin.3,4 Only in 1965, however, was this

disorder brought to the attention of geneticists.5,6Since then numerous additional cases have been

published.714 Despite these clinical articles, however,there are still very little data on the natural history ofWHS. There also tends to be a skewing of informa-tion 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 Acad-

emy of Pediatrics.

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being told that their child has very little chance, ifany, for meaningful interaction with his or her rela-tives and peers; that he will never walk or achievesphincter control; and that he will have a seriousseizure disorder.

The purpose of this article is to help delineatemore thoroughly the natural history of WHS, and toobtain better information to answer parents ques-tions in a clinical setting.

Accurate information is of paramount importance

to obstetricians and pediatricians who assist familiesin making relevant decisions about possible inter-ruption of pregnancy, who help the family adjust tothe birth of a baby with monosomy 4p, and who, inseveral cases, provide health care for many years15,16.

GENERAL CLINICAL DATA

We have evaluated 15 patients in three centerswith the 4p- syndrome. Eleven of these patients aredescribed for the first time. Four (cases 1, 2, 3, and 7)were reported previously17,18; 2 of them (cases 3 and7) showed novel, as yet unreported, clinical findings,such as sensorineural hearing deafness and rightsplit hand.

There were 12 females and 3 males. Age at firstobservation ranged between newborn and 9 years.Eight of the cases, five from Italy and three fromUtah, have been followed from 512years to 16 years.

Thirteen cases were detected by standard cytoge-netics, 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 hybrid-ization (FISH) analyses. In fact, they had been ob-served previously in different university hospitalsand the diagnosis had been missed, because stan-dard 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 confirmedusing FISH probes in the critical Wolf-Hirschhornregion.

All patients were born at term and were small forgestational age. Parental ages were similar to thegeneral population. Pregnancy and family historywere generally unremarkable. Birth history was non-contributory for all but 4 cases, (1, 2, 3, and 15), inwhom some degree of perinatal distress was present.

CLINICAL FINDINGS

The clinical findings of our patients are listed in

Table 1.All of them showed a characteristic craniofacialappearance with microcephaly, some degree of skullasymmetry, the Greek warrior helmet appearanceof the nose, hypertelorism, highly arched eyebrows,distinct mouth with downturned corners (Fig 1), sim-ple or posteriorly angulated ears, preauricular skintags or pits (Fig 2), bilateral cleft lip and palate (Fig 3)or cleft palate, short philtral length and microgna-thia.

All patients showed short stature and slow weightgain (less than third centile), despite adequate caloricand protein intake. In view of severe feeding diffi-culties, 6 Utah patients (cases 4, 6, 9, 11, 12, and 13)

and 1 Italian patient (case 15) underwent gastros-tomy.

Congenital heart lesions, in the form of patentductus arteriosus associated with ventricular septaldefect (case 7) or aortic insufficiency (case 13), iso-lated atrial septal defect (cases 5 and 12) and pulmo-nary stenosis (case 15) were found in 5 patients.

Bladder exstrophy and obstructive uropathy wereobserved in only 1 patient (case 13), while chronicurinary tract infections secondary to vesicoureteral

reflux were reported in another (case 12).Four Utah patients (cases 4, 6, 10, and 13) showedconduction hearing defects, attributable to very fre-quent otitis media, whereas bilateral sensorineuralhearing loss was diagnosed in 1 Italian patient (case3) at 15 months of age.

A variety of skeletal anomalies were found in66.6% of the patients. Those consisted of right splithand (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-likeappearance of the thumb, and thin fingers with bi-lateral 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 severelydelayed bone age was found, together with a numberof anomalies, such as craniostenosis with brachyce-phalic skull, small iliac alae with coxa valga sub-luxans (case 2), double first phalanx of the first ray ofthe left foot and absence of the ossification nucleusfor the ulnar styloid apophysis (case 3), and lack ofpubic bone ossification (case 15).

Abnormal tooth development was present in the 4Italian patients checked for it. There were agenesis ofthe lower lateral incisors and of the right uppercanine (case 1); delayed tooth eruption with persis-

tence of deciduous teeth at 9 years (cases 2 and 15);and peg-shaped teeth (case 3).

Skin changes were observed in most patients, andwere characterized by cutis marmorata, dry skin, orhemangioma. 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 regularmenses.

NEUROLOGIC FINDINGS

Thirteen of our patients had seizures, starting be-

tween 5 to 23 months of age, with an obvious peakincidence at around 9 to 10 months. Seizures wereeither unilateral clonic, with or without secondarygeneralization, or generalized tonic clonic from the

beginning; they were mostly facilitated by fever, onoccasions lasting 15 minutes, and often occurred inclusters.

Unilateral or generalized, prolonged clonic or ton-ic-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 accom-panied by a mild myoclonic component, were ob-served in 9 patients (cases 1, 3, 4, 6, 11, 12, 13, 14, and

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

Case 1 Case 2 Case 3 Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 Case 11

Age at the LastExamination

9 Years6 Months

12 Years 16 Years 4 Years9 Months

1 Year9 Months

3 Years5 Months

1 Year5 Months

9 Years 6 Months 16 Years 2 Years10 Month

Sex F F F F F M F F M F FIntrauterine 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

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15), by 1 to 5 years of age. These were well-controlledby the usual antiepileptic drugs.

In the 7 older patients (cases 1, 2, 3, 8, 10, 12, and15, ranging in age from 9 to 16 years) seizures hadstopped 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 distinctiveabnormalities. These included: frequent, ill-defined,high-amplitude, sharp element-spike/wave com-plexes at 2-to 3.5-Hz, usually diffuse, occurring inlong bursts, and activated by slow wave sleep; andfrequent high-amplitude, spikes, polispikes/wavecomplexes at 4- to 6-Hz, over the posterior third ofthe head, often only seen with the eyes closed.19 Suchparoxysms were accompanied by recognizable clini-

cal changes (atypical absences) in a minority of pa-tients, only in early years, and could be observed formany years even after seizures had stopped.

Brain magnetic resonance imaging (MRI) studieswere conducted on 6 patients. In 3 (cases 1, 2, and 3)there were multifocal white matter hyperintensityareas in T2-weighted images, probably related to theperinatal distress; in 2 patients (cases 4 and 14) therewas thinning of the corpus callosum, associated, incase 4, with diffusely decreased volume of the whitematter, and in 1 patient (case 15) corpus callosum

agenesis was observed. Computed tomography (CT)

Fig 1. Case 5, at 1 year 9 months of age, showing the typicalGreek warrior helmet appearance of the nose, hypertelorism,highly arched eyebrows, repaired cleft lip, distinct mouth withdownturned corners.

Fig 2. Case 5, at 7 weeks of age, showing preauricular skin tagsand posteriorly angulated left ear.

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

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



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of the brain was performed in 2 patients (cases 7 and11) and, while showing enlargement of the lateraland third ventricles with areas of periventricularcystic change anteriorly in case 7, was normal in case11.

Hypotonia and muscle hypotrophy, particularly ofthe lower limbs, were observed in almost all patients.

Stereotypies, such as holding the hands in front ofthe face, hand-washing or flapping, patting self onchest, rocking, head-shaking, and stretching of legs

were observed in 12 patients (Fig 5).DEVELOPMENTAL FINDINGS

All but the youngest patient, who is currently 6months old, had severe to profound developmen-tal delay and mental retardation, with absence ofspeech, which, in the older cases, was limited to

babbling or guttural sounds, occasionally modu-lated in a communicative way. Comprehensionwas limited to simple orders or to a specific con-text.

An intention to communicate appeared to bepresent, to some extent, in 9 patients, but was poor orabsent, in the early years, in 5. In particular the latterdid not smile in response to seeing their mother, didnot look at her while being breastfed, did not followwith their eyes, and often reacted by crying to boththe human face and voice. As discussed below, thisdisorder of affect tended to improve over time.

Two children from Utah (cases 4 and 10) walkedwith support by age 4 and 12 years, respectively. Theoldest child (case 10) is also a self-feeder, and helpsin dressing and undressing herself, but has nographic abilities.

Three patients from Italy (cases 1, 3, and 14) and1 more Utah patient (case 12) walked alone at ages5 years 9 months, 4 years, 5 years, and 7 years,

respectively. Presently, at age 912, 16, 712, and 11years, respectively, all walk with a broad-basedgait and with poor swinging movements of theupper limbs. Two of the 3 Italian patients (cases 1and 3) achieved sphincter control, only during theday, at ages 8 years 9 months and 14 years, respec-tively. Their graphic abilities were limited to scrib-

bling, and they occasionally helped to set and clearthe dinner table, bring a spoon with some food totheir mouths, and dress and undress themselves.

The follow-up of our patients, spanning 16 years,showed that the disorder of affect, observed in 5 ofthem, tended to improve over time, as did the motorabilities.

On the whole there has been an evolution from theaffective point of view, with improved abilities ofadaptation to new situations and an initial differen-tiation of the I processes. An improvement in thecommunicative abilities and verbal comprehensionwith extension of the gesture repertoire and a de-crease occurrence of withdrawal and anxiety behav-iors was also observed.

DISCUSSION

Children with WHS often do face serious phys-ical disabilities, such as failure to thrive, respira-tory problems, club feet, and hard-to-control sei-zures. Both doctors and parents have, then, to dealwith difficult decisions regarding the care of thechild.

Why operate to correct club feet on a child whowill never learn to walk?, Should we operate tocorrect a severe kyphosis-scoliosis in a child withsevere mental retardation?: these are only some ofthe complex questions facing both doctors and fam-ilies.20 It is, therefore, of the utmost importance thatup-to-date information be available in the literature.

This can prove to be an invaluable resource to med-ical professionals and families.

Our experience with the natural history of WHSexpands literature reports, particularly on some is-sues.

All patients have the characteristic facial pheno-type, which, while slightly changing over time,remains easy to recognize into adolescence (Fig 6).

One of the major concerns for parents of childrenwith 4p- and for professionals involved in theircare is the occurrence of seizures. They are ob-served in 50% to 100% of cases.9,10,12,13 Althoughinitially difficult to control in some of them, they

eventually tend to disappear with age, as shown inour patients.In the medical literature very little is known about

the EEG findings in WHS.8,21 Our data show thatpatients with WHS have fairly distinctive EEG fea-tures, outlasting seizures, and not necessarily relatedto them.19 We feel that this observation could behighly relevant to improve medical treatment of suchpatients, who, on some occasions (case 10), despitehaving been seizure-free for quite a long time, arestill given antiepileptic drugs, because of such strik-ing EEG abnormalities.

The brain MRI/CT findings observed in our cases4, 14, 15, and 7 seem to extend the scant neuropatho-

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



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

Therefore, we would suggest serious considerationof neuroimaging studies in all such patients, todeepen our knowledge on the underlying brain pa-thology.

In addition to seizures the other most consistentmedical problem of infancy is major feeding diffi-culty. Six of the Utah patients required gastrostomyin infancy to protect the airway, while 1 Italian pa-tient received gastrostomy only at 4 years 8 months

of age (weight, 6800 g) with a consequent consider-able improvement in weight gain and motor abilities.Gastroesophageal reflux is also common. We wouldsuggest that infants with 4p- who have feeding dif-ficulties receive swallow studies and early consider-ation for gastrostomy tube use.

Although in the past there have been some at-tempts at relating the size of the chromosomal dele-tion to the clinical features, it is now clear that vari-ations in deletions of the short arm of chromosome 4do not result in detectable differences in the pheno-type.2527 It seems, then, even more interesting to notethat 4 of our patients (cases 1, 3, 12, and 14), who

achieved somewhat advanced developmental mile-stones compared with other cases, were detected byregular G-banding (cases 1, 12, and 14) and FISHanalysis (case 3), respectively.

This, again, suggests that it is not necessarily thesmaller deletion that accounts for a less severe out-come. Such a lack of correlation between clinicalseverity and size of the deleted segment might reflectthe actual number and/or the specific function ofgenes in the additionally deleted region. It is of notethat molecular genetic studies have delineated aWHS critical region of approximately 165 kbp in the4p16.3 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 becomponent manifestations of WHS. It might then beadvisable to carry out a proper audiologic examina-tion of such patients, to rule out a possible hearingimpairment, which, if not recognized, might worsenthe 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 havea severe or profound degree of mental retardation,it is evident to us that there is more acquisition ofmilestones than suggested by the medical litera-ture.28 In fact, contrary to what conventionallystated, 6 of our patients were able to walk eitheralone (cases 1, 3, 12, and 14) or with support (cases4 and 10); 3 of them (cases 1, 3, and 10) werecapable of performing simple household tasks,feeding, dressing, and undressing themselves tosome extent; and 2 of them (cases 1 and 3) becametoilet trained by day.

Our series consists of 12 females and 3 males. This

female predominance of cases has been noted in theliterature.29 In recent years guidelines for routinehealth supervision in the primary care setting have

been proposed for children with various syn-dromes.30 From this context we would suggest thefollowing for routine care of infants and childrenwith 4p-:

Infancy-focused examination of the heart; oph-thamology consultation; audiologic screening; de-velopmental testing/referral for early interven-tion; renal ultrasound; swallowing study (if anyfeeding difficulties); EEG (if seizures).

Fig 6. Frontal views at different agesof some of our patients, from infancy(A, at 3 months of age; B, at 5 monthsof age), through childhood (C, at 1 year4 months of age; D, at 1 year 9 monthsof age; E, at 2 years 10 months of age; F,at 3 years of age; G, at 3 years 8 monthsof age; H, at 6 years of age; I, at 9 yearsof age, J, at 9 years of age), to adoles-cence (K, at 12 years of age; L, at 14years of age; M, at 16 years of age). Athrough M, starting from upper left,looking from left to right. Figures 6G,6I, and 6L were reproduced with per-mission from the following article: Bat-taglia A. Riv Ital Pediatr (IJP). 1997;23:254259.



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Childhood-continued developmental testing/appropriate school placement; follow-up EEG (ifseizures).

Participation in support groups is an importantstrategy for many parents in the coping with a childwith disabilities.31 The parents of the Utah cases

banded together to form a local parent supportgroup. There are two existing support organizationsin North America for families of children with 4p-:The Wolf-Hirshhorn Syndrome Network and the

Support Organization for Trisomy 18,13, and RelatedDisorders (SOFT). These groups can be contactedthrough the Internet.

Although WHS is widely considered to be a deletionsyndrome,32 we believe that there might be quite anumber of yet unrecognized and misdiagnosed casesin which there is a microdeletion, not shown on stan-dard cytogenetics. We wish to stress the serious diffi-culty encountered in confirming the provisional clinicaldiagnosis in such patients (see our cases 2 and 3) and toalert clinicians and make them cognizant of the need topursue high-resolution banding and molecular analy-ses (FISH) in suspect WHS cases. We think that the

condition is less rare than actually thought.

Agatino Battaglia, MD*John C. Carey, MDPeeches Cederholm, BSDavid H. Viskochil, MD, PhDArthur R. Brothman, PhDCinzia Galasso, MD*Stella Maris Scientific Research InstituteInstitute of Child Neurology and PsychiatryUniversity of Pisa256018 Calambrone, Pisa, ItalyDivision of Medical GeneticsDepartment of Pediatrics

University of Utah Health Sciences CenterSalt Lake City, UT 84132Institute of PediatricsUniversity of RomeS Eugenio HospitalRome, Italy 00100

ACKNOWLEDGMENTS

This work was supported in part by the International Programfor Consultation and Research in Clinical Genetics of the Univer-sity of Utah.

We thank the families of the children with WHS who kindlyparticipated in our project.

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1999;103;830PediatricsBrothman and Cinzia Galasso

Agatino Battaglia, John C. Carey, Peeches Cederholm, David H. Viskochil, Arthur R.Natural History of Wolf-Hirschhorn Syndrome: Experience With 15 Cases

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Wolf Hirschhorn 15

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