American Journal of Medical Genetics 132A:320–323 (2005)

Clinical ReportNatural History of Cardiac Involvement inGeleophysic DysplasiaA. Scott,1 S. Yeung,2 D.F. Dickinson,3 G. Karbani,4 and Y.J. Crow4*1School of Medicine, University of Leeds, United Kingdom2Department of Paediatrics, St. Luke’s Hospital, Bradford, United Kingdom3Department of Paediatric Cardiology, Leeds General Infirmary, Leeds, United Kingdom4Department of Clinical Genetics, St. James’s University Hospital, Leeds, United Kingdom

Geleophysic dysplasia is an autosomal recessiveshort-limbed, dysmorphic syndrome. The con-dition is frequently associated with cardiacvalvular disease, which may result in secondaryhypertrophy and cardiac failure. We describe twodistantly related Pakistani children with classicalfeatures of geleophysic dysplasia. Pulmonarystenosis was recognized in both within a fewmonths of birth. The younger child shows no signsof cardiac decompensation at the age of 7 yearswhilst her older cousin has developed a signi-ficant pulmonary gradient requiring surgicalintervention in the second decade of life. Thenatural history of his disorder highlights thatthe cardiac involvement seen in apparently stableforms of geleophysic dysplasia is frequentlyprogressive. � 2004 Wiley-Liss, Inc.

KEY WORDS: geleophysic dysplasia; cardiacvalvular disease; pulmonary ste-nosis

INTRODUCTION

Geleophysic dysplasia is a rare, autosomal recessivedisordercharacterized by short stature, small hands and feet, hepato-megaly, progressive cardiac valvular disease, and a distinctivefacial appearance. To date, at least 26 cases of geleophysicdysplasia have been reported [Vanace et al., 1960; Sprangeret al., 1971, 1984a,b; Koiffmann et al., 1984; Lipson et al.,1987; Shohat et al., 1990; Wraith et al., 1990; Rosseret al., 1995; Pontz et al., 1996; Rennie et al., 1997; Santolayaet al., 1997; Titomanlio et al., 1999; Keret et al., 2002;Matsui et al., 2002].

Herein, we describe two children, third cousins born toconsanguineous parents, now aged 15 and 7 years. In the olderchild, the development of significant pulmonary stenosis in thesecond decade of life suggests that the cardiac involvementseen inapparently stable forms of geleophysic dysplasiamay infact be progressive. We discuss the literature in respect of thecardiac involvement seen in this disease.

CLINICAL REPORT

Patient 1

This boy was born at 33 weeks of gestation by caesareansection to first cousin parents. He is the second child of four,having three sisters who all are alive and well. The pregnancywas characterized by polyhydramnios. Birth weight was1.98 kg and reduced abduction of the hips was noted afterdelivery. At birth his head circumference and weight were onthe50th centile but at 4months bothhad fallen to below the3rdcentile. His length at birth was less than the 3rd centile, limbswere noted to be rhizomelic, and his hands and feet wereobviously small and broad.

As an infant he fed poorlywith slowweight gain and sufferedfrom recurrent respiratory infections. Within the 1st year oflife hehad four admissions to hospitalwith chest infections andright upper lobe atelectasis. Investigations at age 2 monthsincluding renal and cranial ultrasound, barium swallow,thyroid function tests, chromosomes, serum immunoglobulins,mucopolysaccharides, very long chain fatty acids, andbroncho-scopy were all normal.

He has a distinctive facial appearance with a flat philtrum,thin vermillion of the upper lip, long eye lashes, and upslantingpalpebral fissures (Fig. 1). His hands and feet are small andbroad. Skeletal survey performed at age 9 years showed that allbones of the hands, feet, and upper limbs were shorter thannormal and somewhat broad. Throughout childhood, weight,length, and head circumference consistently grew parallel to,but considerablybelow the3rd centile.Hehasnovisceromegaly.

At birth, a grade 3 systolic murmur was heard maximally inthe pulmonic area with conduction to the lungs. Pulmonicstenosis was diagnosed at age 2 months with a gradient of45 mmHg across the right ventricular outlet. He was acya-notic, hadnormal peripheral pulses, and therewasno evidenceof right ventricular hypertrophy or cardiac failure. ECGdemonstrated right axis deviation. At 6 months, a repeatechocardiogram showed that the gradient across the pulmonicvalve had remained stable but there was now evidence of rightventricular hypertrophy. At 9 years cardiac ultrasonographyshowed progressive thickening of the pulmonic valve with aslight increase in the gradient across the right ventricularoutlet to 50 mmHg. He was aymptomatic at this time. At14 years the patient was complaining of shortness of breath onexertion, for example, climbing stairs. Echocardiographydemonstrated an increase in the pulmonary gradient to70 mmHg and the right ventricular pressure was now esti-mated at around 90mmHg. He underwent balloon pulmonaryvalvuloplasty resulting in a reduction in the pulmonarygradient to 30 mmHg.

At the age of 8 years orthopedic problems were noted withsevere limitation of flexion of his hands, fixed plantar flexion

*Correspondence to: Dr. Y.J. Crow, Department of ClinicalGenetics, St. James’s University Hospital, Leeds, LS9 7TF,United Kingdom. E-mail: yanick.crow@leedsth.nhs.uk

Received 14 May 2004; Accepted 5 August 2004

DOI 10.1002/ajmg.a.30450

� 2004 Wiley-Liss, Inc.

deformity of his right foot, and early restriction of dorsiflexionon the left side.Hewalked on tiptoewith a compensatory pelvictilt (Fig. 2). By the age of 10 years there was limited supinationand pronation of his forearms and hewas unable to extend andraise his arms above his shoulders. He now has a poor gripand is unable to make a fist necessitating the use of specialpens and cutlery. He experiences particular difficulty withbuttons and requires help with his trousers when toileting.

His development has been essentially normal apart from adegree of expressive language delay. Thiswas at least partiallyattributed to a conductive hearing loss for which he underwentgrommet insertion aged 5 years. However, despite speech andlanguage therapy he continues to have some difficulty in thisarea. At school he is making slow progress and requires a full-time support assistant for help with reading and writing.

Patient 2

This female child is a third cousin to patient 1, both childrensharing the same great grandmother. She was born at term tofirst cousin parents andhas one younger sisterwho is alive andwell. There were no problems during the pregnancy but she

required suction delivery because of failure to progress. Atbirth she weighed 2.8 kg, her head circumference was 34.1 cm,and her length was 43.6 cm, all below the 50th centile. Afterdelivery shewas noticed to have an unusual facial appearance,symmetrically short limbs, small, square hands, and feet withshort, stubby digits. Shewas considered to have thickened skinbut no visceromegaly. In addition, a grade 2/6 systolic murmurat the left sternal edge was heard.

At age 9 weeks, her weight had fallen below the 2nd centile.She was noted to have a flat mid-face, smooth philtrum, thinupper lip vermillion, and upslanting palpebral fissures. At theage of 7 years, these features remain (Fig. 3). Results frommetabolic testing, chromosome G-banding, and brain scanwere all normal.

At 1 month she demonstrated limited joint movementespecially in the shoulders and hips. She was also unable tofullydorsiflexher feet and in the supinepositionhadpoor reachagainst gravity and difficulty bringing her hands to themidline. At age 4 years she was noted to have contractures ofher elbows, hips, knees, and ankles. She now stands on tiptoeand when her feet are flat she is bent at the knees and hips. Arecent skeletal survey showed that the tubular bones are allshort and relatively broad (Fig. 4). Aged 7 years, she isdescribed as ‘‘bright’’.

Echocardiography performed at age 2 months documentedanostiumsecundumatrial septal defect, patent ductus arterio-sus, prolapsing anterior leaf of mitral valve, and pulmonicstenosis. Recent cardiovascular investigations aged 7 yearsshow that she has a grade 3/6 systolic murmur in the precor-dium due to pulmonary stenosis. She remains asymptomatic.

Fig. 1. Patient 1 with typical facial appearance of geleophysic dysplasiawith a flat mid-face, smooth philtrum, thin upper lip vermillion, andupslantingpalpebral fissures. [Color figure canbeviewed in the online issue,which is available at www.interscience.wiley.com.]

Fig. 2. Contractures at the hip, knee, and ankle in Patient 1. [Colorfigure can be viewed in the online issue, which is available at www.in-terscience. wiley.com.]

Fig. 3. Typical facial characteristics of geleophysic dysplasia inPatient 2. [Color figure can be viewed in the online issue, which is availableat www.interscience.wiley.com.]

Fig. 4. Upper limb radiograph in Patient 2 showing shortened andrelatively broad tubular bones.

Cardiac Involvement in Geleophysic Dysplasia 321

TABLE

I.Summary

ofCard

iacAnom

alies

in28Patien

tsWithGeleo

physicDysp

lasia

Author

Case

Sex

Card

iacinvolvem

ent

(ageatrecognition)

Valve(s)

Progression(age)

Card

iacfailure

(age)

Agelast

reported

(yea

rs)

Dea

th(age)

Hep

atomeg

aly

Vanace

etal.[1960]

1M

Y(5

yea

rs)

P,M

YY

(Diedfrom

)5yea

rs4

mon

ths

Y

Spranger

etal.[1971]

1F

N6

N2*

MY

(10mon

ths)

A,M

Y(22mon

ths)

12

Yþ

LV

hypertrop

hy

5yea

rs12yea

rsSpranger

etal.[1984a]

3*

FY

(1mon

th)

Allvalves

abnormalat

autopsy

Y(13mon

ths)

1mon

th4½

4½

yea

rsNK

Again

(3yea

rs)

4*

FY

(birth)

ASD,PDA

Stillborn

YSpranger

etal.[1984b]

1F

Y(12yea

rs)

M12

YKoiffmannet

al.[1984]

1F

Y(11yea

rs)

A11

Y2*

FProbable

Y(D

iedfrom

)3yea

rsNK

Lipsonet

al.[1987]

1M

Y(4

yea

rs)

M,T

Y(6

yea

rs)

7Y

Wraithet

al.[1990]

1M

Y(birth)

T,P

Y(D

iedfrom

)5mon

ths

N2

FY

(10yea

rs)

MY

(10yea

rs)

11yea

rsY

þLV

hypertrop

hy

Shoh

atet

al.[1990]

1M

Y(ageNK)

M,T

No

No

3½

3½

yea

rsY

2M

Y(ageNK)

MNo

No

17

Y3

MY

(ageNK)

MNo

No

21

Y4*

MY

(ageNK)

A,P

Y(6

yea

rs)

7½

Y5*

FY

(10mon

ths)

M,A

Y(18mon

ths)

2N

þLV

hypertrop

hy

Rosseret

al.[1995]

1*

MY

(birth)

ANon

e(at3yea

rs)

4N

2*

MY

(birth)

A,M

23

MY

(ageNK)

M7

YPon

tzet

al.[1996]

1M

Y(11½

yea

rs)

Systolic

murm

ur

11½

Y2*

MN

8½

N3*

FN

8N

Santolayaet

al.[1997]

1M

N6

Y2

MN

11

NRen

nie

etal.[1997]

1M

N2

NTitom

anlioet

al.[1999]

1M

Y(8

mon

ths)

A,M,T,P

Y(5

yea

rs)

7Y

Presentcases2003

1M

Y(birth)

PY

(14yea

rs)

15

Nþ

RV

hypertrop

hy

2F

Y(birth)

Ostium

secu

ndum

septal

defect,PDA,M,P

Y(7

yea

rs)

7N

*Siblings;Y,yes

present;N,n

otpresent;NK,n

otknow

n;P

,pulm

onary

valve;M,m

itralv

alve;A,aorticvalve;LV,leftven

tricular;ASD,atrialsep

tald

efect;PDA,p

atentductusarteriosu

s;T,tricu

spid

valve;RV,

rightven

tricular.

DISCUSSION

Geleophysic dysplasia presents with short-limbed growthrestriction, small hands and feet (as a result of shortenedtubular bones), brachydactyly, joint contractures, tiptoe gait,thickened skin, and a good-natured ‘‘happy’’ facial appearance.Affected children have a round, full face, small nose withanteverted nostrils, broad nasal bridge, upward slant of thepalpebral fissures and a long, thin upper lip with flat philtrum.The basic biochemical defect involved in geleophysic dysplasiais unknown but there is evidence to suggest a primary disorderof intracellular glycoprotein metabolism [Lipson et al., 1987;Wraith et al., 1990]. It has been suggested that an accumula-tion of storage material in the extracellular matrix of cartilageand other tissues might explain the disturbed growth, jointcontractures, and cardiac valve involvement observed inaffected individuals [Pontz et al., 1996].

In view of the typical facial appearance, short stature withsmall hands and feet, joint contractures, cardiac involvement,and the presence of consanguinity there is little doubt that thetwo children described here have geleophysic dysplasia. Asreported by other authors (Table I), our cases illustrate thathepatomegaly is not always present in this disorder.

The first published case of geleophysic dysplasia was that ofVanace et al. [1960], who described an ’atypical form ofgargoylism‘ leading to the death of the patient aged 5 yearsfromheart failure. Further cases demonstrating an early onsetand aggressive course of cardiac involvement resulting indeath within the first 6 years of life have also been reported[Koiffmann et al., 1984; Spranger et al., 1984a; Wraith et al.,1990]. However, although signs of valvular thickening arefrequently present in the early years, most published caseshave not developed significant cardiac disease at least untiltheir second decade (Table I). Patient 1 described hereinconforms to this pattern.

Lipson et al. [1987] postulated that a severe and inter-mediate form of geleophysic dysplasia might exist in respect ofthe degree of cardiac involvement. However, we note that twochildren presenting with life-limiting valvular disease withinthe 1st year of life [Koiffmann et al., 1984; Spranger et al.,1984a] had siblings whose cardiac involvement was lessaggressive. These reports suggest that factors other than thespecific familial mutation determine the degree of cardiacinvolvement.

A recent 7-year follow-up by Titomanlio et al. [1999]described apatientwith cardiac involvement thatwasdetectedin the 1st year of life and, although deteriorating initially, wassubsequently non-progressive with the pulmonary stenosisactually improving. We also note Cases 2 and 3 reported byShohat et al. [1990] with apparently stable valvular disease attheages of 17and21years, respectively.Patient 1 in this report

is now 14-year-old. The natural history of his disorder suggeststhat the cardiac involvement even in apparently ‘‘milder’’forms of geleophysic dysplasia can remain stable for manyyears but subsequently progress.With this inmind it would beinteresting to have further information on other patients suchas those reported by Shohat et al. [1990], Titomanlio et al.[1999], Santolaya et al. [1997], and Pontz et al. [1996].Although it is not possible to predict the course of cardiacinvolvement ingeleophysic dysplasia, our reporthighlights theimportance of continued cardiac surveillance in this disorder.

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Lipson AH, Kan AE, Kozlowski K. 1987. Geleophysic dysplasia—acromicricdysplasiawith evidence of glycoprotein storage.AmJMedGenet [Suppl]3:181–189.

Matsui Y, Kawabata H, Yasui N. 2002. Multiple trigger fingers associatedwith geleophysic dysplasia. Arch Orthop Trauma Surg 122:371–372.

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ShohatM,GruberHE,PagonRA,Witcoff LJ,LachmanR,FerryD,FlaumE,RimoinDL. 1990.Geleophysic dysplasia:A storagedisorder affecting theskin, bone, liver, heart and trachea. J Pediatr 117:227–232.

Spranger JW, Gilbert EF, Tuffli GA, Rossiter FP, Opitz JM. 1971. Geleo-physic dwarfism—a ‘focal’ mucopolysaccharidosis? Lancet 2:97–98.

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Spranger J, Gilbert EF, Flatz S, BurdelskiM,Kallfelz HC. 1984b. Acrofacialdysplasia resembling geleophysic dysplasia. Am J Med Genet 19:501–506.

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