A R T I C L E

Health Supervision and Anticipatory Guidance ofIndividuals With Wolf-Hirschhorn SyndromeAGATINO BATTAGLIA* AND JOHN C. CAREY

Wolf-Hirschhorn syndrome (WHS) is a well-known malformation syndrome due to microdeletion of theshort arm of chromosome 4 (4p1). Almost 120 cases have been reported so far, yet there is still limitedinformation on its natural history. It is generally thought that these children have severe developmentaldisabilities and tend to be mere survivors devoid of personality. It is evident to us [Battaglia et al., 1999a,1999b], however, that individuals with WHS are capable of greater psychomotor development than pre-viously suggested [Guthrie et al., 1971]. Thus, it is even more important to establish guidelines for healthsupervision and anticipatory guidance of such patients. This would help professionals and families indeveloping the most appropriate individualized plan for each child, in order to allow the maximumachievement possible. In the present article we propose guidelines for health supervision and anticipatoryguidance of individuals with WHS. These guidelines derive from our experience with the natural history ofseveral children, adolescents, and adults with WHS, gained through the literature, personal observation,and contacts with the national support groups in North America and Italy. Am. J. Med. Genet. (Semin. Med.Genet.) 89:111–115, 1999. Q 1999 Wiley-Liss, Inc.

KEY WORDS: Wolf-Hirschhorn syndrome; del(4p) syndrome; health maintenance; health supervision; anticipatory guidance

INTRODUCTION

The access to at least a basic level ofservices to promote health and treat ill-ness is a right of every person. Over thepast 20 years, a new model of clinicalcare for individuals with genetic disor-ders has emerged from the disciplines of

medical genetics, pediatrics, and neu-rology [Carey, 1992]. By now, childhealth supervision has been establishedas part of the foundation of pediatricclinical practice [Green, 1985; Char-ney, 1986]. Child health supervision isimportant in terms of performing ap-propriate screenings, applying specificpreventive measures, and developing arelationship with the family. The main-stay of care is anticipatory guidance andsurveillance for treatable complications.Anticipatory guidance provides a pre-ventive measure involving health edu-cation and parent counseling. TheAmerican Academy of Pediatrics pre-pared guidelines for health supervision,listing the important themes for antici-patory guidance at periodic health su-pervision visits [Green, 1985].

The pediatric practitioner has sev-eral qualifications that place him or herin an advantageous position to care forthe child with a genetic disorder. Thepediatrician is a primary caregiver and aspecialist in the health concerns of chil-dren. In addition, this person has usu-ally invested time in gaining the rapportand trust of the family and is in a uniqueposition to understand the impact of thedisorder on family dynamics. For suchreasons, the pediatrician is the ideal

practitioner to coordinate the impor-tant, continuous, and comprehensivecare of the child with a genetic disor-der. This can be done by workingclosely with the various specialists whoare involved from time to time, accord-ing to the child’s main health needs.Thorough knowledge of the naturalhistory of the disorder is essential.

BASIC PRINCIPLES FORHEALTH MAINTENANCEAND SUPERVISION

The first crucial issue in the initial plan-ning of health care management for apatient with a malformation syndromeis correct diagnosis; the second one isknowledge of the natural history. Ac-

Dr. Agatino Battaglia is a pediatric neu-rologist, working at the Stella Maris Sci-entific Research Institute, which dealswith patients less than 18 years of agewith neuropsychiatric and developmen-tal disorders. Dr. Battaglia is head of theCenter for Congenital Malformation Syn-dromes of the institute, currently study-ing recognizable patterns of human mal-formation that have neuropsychiatric ab-normal i t ie s and genet i c factor sunderlying neuropsychiatric and devel-opmental disorders. He has been work-ing together with Prof. Giovanni Nerisince 1992, with Dr. John C. Carey since1995, and with Dr. John M. Opitz since1998. Dr. John C. Carey is a clinical ge-neticist, professor of pediatrics, and chiefof the Division of Medical Genetics, De-partment of Pediatrics, University ofUtah Health Sciences Center.

Contract grant sponsor: Interna-tional Program for Consultation and Re-search in Clinical Genetics of the Univer-sity of Utah.

*Correspondence to: Stella MarisScientific Research Institute, Institute ofChild Neurology and Psychiatry, Univer-sity of Pisa, via dei Giacinti 2, 56018,Calambrone (Pisa) , I ta ly . E-mai l :abattaglia@inpe.unipi.it

The pediatrician is theideal practitioner to

coordinate the important,continuous and

comprehensive care of thechild presenting a genetic

disorder.

AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 89:111–115 (1999)

© 1999 Wiley-Liss, Inc.

curate diagnosis is of the utmost impor-tance for the individual, the family, andthe practitioner. Although the labelingprocess might seem stigmatizing, diag-nosis provides prediction, and it is oftensought by the family members, whowant to know why and how it hap-pened and if it will happen again. Pre-cise diagnosis may help establish an ac-curate recurrence risk, predict the prog-nosis with relative certainty, andorganize appropriate laboratory testing,avoiding a diagnostic evaluation of un-necessary complexity, expense, and in-vasiveness. The diagnosis and the

knowledge of the natural history to-gether make it possible to plan specificmanagement and treatment. Theguidelines for health maintenance andsupervision prove to be of invaluablehelp at this point. Knowing the precisediagnosis and natural history of the con-dition affecting a child may help thefamily in coping with the potential se-rious manifestations and/or develop-mental disabilities. Additional help maycome from the pediatrician or the spe-cialist taking care of the child, throughlistening to the family’s main concerns,addressing these concerns wheneverpossible, and validating and sharingtheir feelings. Referral to parent sup-port groups, the strong stimulus andsupport to initiate a new parent supportgroup [Battaglia et al., 1998], or ar-rangement of a meeting with other par-ents and children with the same disor-der are examples of how much can bedone in the care setting.

THE DEL(4P) SYNDROME

Wolf-Hirschhorn syndrome (WHS),first described in 1961 [Cooper andHirschhorn, 1961], is due to partial de-letion of the short arm of chromosome4. Translocation is responsible for 10–15% of cases [Gorlin et al., 1990]. Therest are de novo deletions of preferentialpaternal origin [Tupler et al., 1992;Dallapiccola et al., 1993]. Although theincidence appears to be about 1/50,000births, with a female predominance[Gorlin et al., 1990], we think thatquite a number of patients are still beingmisdiagnosed and unrecognized [Batta-glia, 1997; Battaglia and Carey, 1998;Battaglia et al., 1999a,b; Wright et al.,1999]. This condition appears to be aserious one, since survival figures indi-cate that at least 35% die during the firsttwo years of life. These figures are bi-ased, and no population study of sur-vival has been performed. Although it isnot widely known, many survive toadulthood [Opitz, 1995; Wheeler et al.,1995; Schaefer et al., 1996]. It is veryimportant to apply the principles ofhealth supervision to the children whodo survive, because some may achievemore advanced psychomotor develop-ment than previously thought [Battagliaet al., 1999a,b]. An updating of ourknowledge of the natural history andoutcome of children with WHS, basedon larger samples, is then indicated.

MAJOR CONCERNS

Two of the major concerns for parentsand professionals dealing with childrenwith WHS are severe feeding difficul-ties and seizures (Table I).

Feeding Difficulties

In spite of adequate calorie and proteinintake, all patients show slow weightgain (always below 2%) [Gorlin et al.,1990; Battaglia et al., 1999a,b]. This maybe due to different problems, such asoral facial clefts, with related difficultyin sucking (almost 50%); poorly coor-dinated swallow, with consequent re-peated aspirations; and gastroesophageal

reflux. While the latter problem is quitecommon in infancy (1/300–1/1,000)and is transitory, it usually persists andresults in a failure to thrive and respira-tory diseases in babies with 4p−. In or-der to (a) sustain weight gain and, con-sequently, general health status, withimprovement of motor abilities; (b)protect the airway; and (c) cope withgastroesophageal reflux; swallowingstudies in infancy and consideration ofgastrostomy tube placement are highlyrecommended. Seven of 15 patients re-cently studied by the authors [Battagliaet al., 1999a,b] who underwent gastros-tomy for severe feeding difficultiesshowed improvement in general health.

Seizures/Electroencephalography

Seizures occur in 50–100% of childrenwith WHS [Guthrie et al., 1971; Cen-terwall et al., 1975; De Grouchy andTurleau, 1984; Stengel-Rutkowski etal., 1984; Battaglia et al., 1999a,b]. Ac-cording to a recent study by the authors[Battaglia et al., 1999a,b] and from an ad-ditional 12 unpublished cases, seizuresstart between 5 and 23 months of age,with a peak incidence at about 9–10months. They are either unilateralclonic or tonic, with or without sec-ondary generalization, or generalizedtonic–clonic from the beginning. Vary-ing degrees of fever frequently triggersuch seizures, which, on occasion, lastmore than 15 min and often happenin clusters. Unilateral or generalized,clonic or tonic–clonic status epilepticus

Despite the reportedfrequency of 1/50,000births with a female

predominance of cases, webelieve that quite a number

of patients withWolf-Hirschhorn syndromeare still being misdiagnosed

and unrecognized.

Although the labelingprocess might seem

stigmatizing, diagnosisprovides prediction, and it

is often definitely sought bythe family, who wants to

know why and how ithappened, and if it will

happen again.

112 AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) ARTICLE

usually occurs in 40% of cases on severaloccasions during the early years, in spiteof adequate antiepileptic treatment. Al-most 50% of patients show atypical ab-sences by 1–5 years of age. Such epi-sodes are sometimes accompanied by amild myoclonic component and arewell controlled by the main antiepilep-tic drugs (namely, valproic acid). In50% of cases, seizures stop by 3–11years of age, and 25% of patients studiedpresently are not receiving medication.

Distinctive abnormalities werefound in 40% of our patients, who un-derwent serial electroencephalographic(EEG) studies over a follow-up periodspanning 18 years [Battaglia et al.,1996]. These abnormalities could beseen for many years after seizures hadstopped and even in one patient whohad never had seizures. Such an obser-vation seems important in the treatmentof patients with WHS who are still re-ceiving antiepileptic drug treatmentsimply because of the striking EEG ab-normalities, in spite of having been sei-zure free for a number of years.

Consequently, we would stress thatwaking/sleeping video–EEG–poly-graphic studies are particularly valuablein infancy and childhood, for the bestcharacterization of seizures. Moreover,in view of the fact that almost 90% ofpatients with WHS have multiple sei-zures, very often triggered by fever, andthat 50% of them later show atypicalabsences (responsive to valproic acid), itseems appropriate to suggest the admin-istration of valproic acid soon after thefirst seizure. Last, since we have foundthat patients with WHS have distinctiveEEG abnormalities that are not neces-sarily correlated with seizures, it alsoseems appropriate to withdraw antiep-ileptic medication gradually in all thosewho have not experienced seizures for5 years [Dean and Penry, 1995].

OTHER MEDICALCOMPLICATIONS

Skeletal Anomalies

Skeletal anomalies are noted in almost70% of patients with WHS [Battaglia et

al., 1999a,b]. These consist of clubfeet,kyphosis–scoliosis, hip dislocation, mal-formed toes and fingers, and, occasion-ally, split hand. Professionals have askedsome parents, “Why operate to correctthe clubfeet of a child who will neverlearn to walk?” Contrary to what isusually stated in the literature, we noware aware that quite a number of indi-viduals with WHS (40% of our sample)[Battaglia et al., 1999a,b] do walk, eitherwith support or alone. In addition,through our contact with the NorthAmerican Wolf-Hirschhorn SyndromeNetwork; the Support Organization forTrisomy 18, 13, and Related Disorders(SOFT); and the Wolf-Hirschhorn Syn-drome Italian Association (AISiWH)[Battaglia et al., 1998], we are nowevaluating more ambulatory individualswith the syndrome. Therefore wewould strongly suggest early referralto specialists for thorough evaluationand treatment of clubfoot, if appro-priate. Similarly, children should rou-tinely be checked for scoliosis and ky-phosis.

Heart Defects and Hearing Loss

Other concerns related to the syndromeare heart defects and hearing loss; in our

experience, these problems are seen in33% of cases [Battaglia et al., 1999a,b].The heart lesions are usually not com-plex, and they can be easily repaired, ifappropriate. On occasion, the patientwill outgrow them. A focused exami-nation of the heart (auscultation/electrocardiography/echocardiogra-phy) is therefore indicated in infancy.

Hearing loss, most often of theconductive type, may also be sensori-neural. When it is conductive in nature,it is caused by chronic serous otitis me-dia. It is usually of a degree that canpotentially affect language acquisitionand educational achievement. In spiteof what is commonly stated in the lit-erature, we are aware of a few patientswith WHS who are able to talk in shortsentences. For this reason, otolaryngo-logical evaluation and audiological

TABLE I. Health Supervision and Anticipatory Guidance of ChildrenWith Wolf-Hirschhorn Syndrome*

Clinical concerns Recommendations for treatment

Feeding difficulties Swallowing studies/gastrostomy tubeSeizures Video–EEG–polygraphic studies/appropriate AEDSkeletal anomalies

Clubfoot Early referral for evaluation and treatment,if appropriate

Scoliosis/kyphosis Routine checkHeart defects Heart auscultation/ECG/echocardiographyHearing loss Otolaryngological evaluation/audiological screeningKidney disorders Renal function testing/renal ultrasound testingOcular anomalies Ophthalmology consultationDevelopmental disabilities

Absent/poor speech Speech evaluationMental retardation Appropriate psychometric evaluationImpaired motoric

aspectsMotoric evaluation → personalized rehabilitation

programEarly intervention/appropriate school placement

*EEG, electroencephalogram; AED, antiepileptic drug; ECG, electrocardiogram.

It is worth noting that13.3% of our patients withWolf-Hirschhorn syndromebecame continent during theday between ages 8 and 14

years.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.) 113

screening are mandatory both in in-fancy and childhood.

Kidney Disorders

Kidney disorders seem to be quite rarein WHS; however, in view of the factthat it is possible to seem healthy with asilent kidney disease, it might be worthcarrying out renal function testing(mostly urinalyses) and renal ultrasono-graphic studies in infancy.

Ocular Abnormalities

Ocular abnormalities (iris/optic nervedefects, cataracts, glaucoma) are presentin almost 30% of patients [Battaglia etal., 1999a, 1999b]; ophthalmology con-sultation is suggested in infancy, even ifthe child has no iris coloboma.

DEVELOPMENTALDISABILITY

While it seems certain that most indi-viduals with WHS have a severe or pro-found degree of mental retardation,with absence of speech, it is evident thatthere are patients with more advancedpsychomotor development than hasbeen suggested previously [Guthrie etal., 1971; Battaglia, 1997; Battaglia etal., 1999a, 1999b]. As stated earlier,40% of our patients [Battaglia et al.,1999a, 1999b] are able to walk, and,through contacts with family supportgroups in the United States and Italy,we are becoming aware of more per-sons able to walk and run and talk inshort sentences. Moreover, although30% of patients show poor or absentintention to communicate in the earlyyears, it is clear that communicationimproves over time in all cases, withextension of the gesture repertoire anddecreased withdrawal. Most individualswith WHS interact and relate to theirfamilies and, generally, to the peoplethey meet. This is of the utmost impor-tance with regard to the possibility ofteaching these children internationalsign language, which does not inhibitthe appearance of speech.

In all cases, there is a slow but con-stant improvement in psychomotor de-velopment, which, in a growing num-

ber of patients, seems to proceed fartherthan ever thought possible. It is worthnoting that 13.3% of our patients[Battaglia et al., 1999a, 1999b] becamecontinent during the day between ages8 and 14 years. This is in contrast to thecommon view held by many profes-sionals that there is no progression ordevelopment in children with this con-dition. Every situation is different, andeach child is unique. We would stressthe right and the need of each patientwith WHS to receive not just the or-dinary care given to any child but alsothe extraordinary care necessary forcopying with the problems of thedel(4p) disorder.

We suggest enrolling these patientsin a personalized rehabilitation pro-gram, which should cover motor as-pects (oral motor and feeding therapyincluded), cognition, communication,and social skills (Table I). Early inter-vention and, later, appropriate schoolplacement are mandatory. Owing tothe paramount importance of betterunderstanding the natural history of thesyndrome, we are now in the process ofevaluating the results of an exhaustivequestionnaire we sent to the families ofchildren with WHS through their na-tional support groups in North Americaand Italy. Bearing in mind what wehave learned up to now, we are confi-dent that the large amount of clinicalinformation we can gain from thisquestionnaire regarding a large sampleof patients with WHS will shed morelight on the true natural history ofWHS.

ACKNOWLEDGMENTS

We thank the families of the childrenwith WHS who taught us so much.

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