, . 17:8: 773–776 (1997)

SHORT COMMUNICATION

RECURRENT SEVERE INFANTILE CORTICALHYPEROSTOSIS (CAFFEY DISEASE) IN SIBLINGS

. 1*, . 1, 2, 3 . 2

1Department of Obstetrics, Gynecology, and Reproductive Sciences, The University of Texas-Houston MedicalSchool, Houston, TX, U.S.A.

2Department of Pediatrics, The University of Texas-Houston Medical School, Houston, TX, U.S.A.3Department of Pathology, The University of Texas-Houston Medical School, Houston, TX, U.S.A.

Received 4 October 1996Revised 13 January 1997Accepted 15 January 1997

SUMMARY

Infantile cortical hyperostosis (ICH), Caffey disease, is a multifocal, inflammatory skeletal process with classiconset before the fifth month of life and resolution by the age of 3 years. A severe phenotype with early prenatal onsethas also been described. Inheritance is generally accepted as autosomal dominant with variable expression andpenetrance. However, occurrence in siblings with no family history has been reported, raising the possibility ofheterogeneity and the existence of a severe autosomal recessive form. We describe a third family with prenatallydiagnosed ICH in two siblings, providing further evidence for this form of inheritance. ? 1997 by John Wiley &Sons, Ltd.

Prenat. Diagn. 17: 773–776, 1997No. of Figures: 2. No. of Tables: 1. No. of References: 10.

: Caffey disease; prenatal diagnosis; inheritance

INTRODUCTION

Infantile cortical hyperostosis (ICH), Caffey dis-ease, is a multifocal, inflammatory skeletal processwith onset before the fifth month of life andresolution by the age of 3 years (Langer andKaufman, 1986). The pathogenesis of ICH isunknown but familial studies suggest an auto-somal dominant aetiology with variable expressiv-ity and penetrance (Saul et al., 1982). Prenatalpresentation of ICH is rare and is frequentlyassociated with a poor prognosis. There are twopublished reports of ICH diagnosed prenatally insiblings with no family history of the disorder(Turnpenny et al., 1993; De Jong and Muller,1995). Here we describe a third example of

prenatal ICH occurring in siblings with no historyof ICH in the parents.

CASE REPORT

A 34-year-old black female and her non-consanguineous husband presented at 22 weeks’gestational age because of suspected hydramnios(case 1). No history of ICH nor a family history ofskeletal dysplasia could be elicited from the patientor her husband. She had two previous spontaneousabortions with a different partner. Targeted ultra-sound confirmed hydramnios with the femurlength at the fifth percentile. Amniocentesis wasperformed and the chromosome results were46,XX. A follow-up ultrasound at 26 weeksrevealed shortening of all extremity long bones.The pregnancy delivered spontaneously at 28weeks, with Apgar scores of 0 and 1 and a birth

*Correspondence to: Beth M. Drinkwater, MS, PrenatalWellness Center, 628 St Andrews Blvd, Charleston, SC 29407,U.S.A. E-mail: wilkesb@musc.edu

CCC 0197–3851/97/080773–04 $17.50? 1997 by John Wiley & Sons, Ltd.

weight of 1000 g. A probable oesophageal cleft,sepsis, poor cardiovascular function, and boweddistal lower extremities were noted. This childexpired on day 10 of life of complications relatedto prematurity, oesophageal abnormalities, andrespiratory difficulties. Autopsy revealed skeletalfindings consistent with ICH. X-ray revealed amottled appearance with periosteal bone depo-sition of all long bones, scapula, and ilia; thecalvarium and spine were unaffected (Fig. 1).In the next pregnancy (case 2), ultrasound per-

formed at 14 weeks’ gestation demonstrated aunilateral bowed femur and mild lower extremityshortening. By 19 weeks, the generalized extremityshortening was more pronounced and a closedlumbosacral neural tube defect was also observed.This pregnancy was terminated at 19 weeks.Autopsy revealed skeletal findings consistent withICH, multiple fractures in the long bones, andirregularities in zones of ossification in the ribsand long bones. X-ray revealed exuberant newperiosteal bone deposition of all long bones, withthe calvarium and spine unaffected (Fig. 2).

DISCUSSION

Two distinct forms of ICH have been identified.The first, or classical form, has an average ageof clinical onset at 10 weeks of life with pain-ful swelling of soft tissues in one or more areas,fever, irritability, and decreased movement of theaffected bones (Saul et al., 1982). Radiologically,

subperiosteal cortical thickening occurs beneathareas of soft tissue swelling and the marrow cavityappears to be encroached upon by dense corticalbone. Spontaneous healing ensues with normalcortical bone formation and by 3 years there isusually no trace of the process, though casespersisting into adulthood have been described(Turnpenny et al., 1993). The most frequentlyaffected bone is the mandible (80 per cent) fol-lowed by the clavicle, tibia, ulna, femur, rib,humerus, maxilla, and fibula. Histologically, thelesions represent periosteal inflammation progress-ing to new bone formation, usually with resolutionby 1 year of age (Saul et al., 1982).The second type, which has been diagnosed

prenatally, shows a more severe phenotype charac-terized by hydramnios, extensive skeletal involve-ment, and oedematous and sometimes shortextremities. Histological and radiological findingsare similar to those in classical ICH, with thicken-ing of the periosteum, extensive new periosteal

Fig. 1

Fig. 2

774 . . .

. ., . 17: 773–776 (1997) ? 1997 by John Wiley & Sons, Ltd.

bone formation, and marked cortical hyperostosis.Integrity of the spine, hands, and feet and relativesparing of the metaphyses are characteristic.Angulation deformities of the long bones may bepresent; this has not been demonstrated in thepostnatal form (Lecolier et al., 1992). Survival withsevere prenatal ICH has been reported when thepregnancy reached term, the outcome being similarto later-onset cases with gradual resolution in earlychildhood (Barba and Freriks, 1953; Scharer andSzabo, 1966; Turnpenny et al., 1993). A typicalphenotype of severe prenatal ICH has yet to bedefined due to its rarity; the diagnosis is usuallymade on the basis of the radiological findings. Ofthe 13 prenatally diagnosed cases reported, 11 havemanifested the severe phenotype characterized byhydramnios and extensive skeletal involvement(Jenkinson et al., 1943; Barba and Frericks, 1953;Faul, 1961; Scharer and Szabo, 1966; Labrune

et al., 1983; Langer and Kaufman, 1986; Lecolieret al., 1992; Turnpenny et al., 1993; De Jong andMuller, 1995) (Table I). The cause of the associ-ated hydramnios is unknown. Oedema or hydropswas noted in the cases presented by Langer andKaufman, Lecolier et al., Turnpenny et al. (cases 1and 2), and De Jong and Muller (case 1). Thecause of the oedema/hydrops is also unknown.ICH is difficult to diagnose prenatally. The

differential diagnosis includes hypophosphatasia,camptomelic dysplasia, and osteogenesis imper-fecta (OI). Hypophosphatasia is characterized bypoor mineralization, not seen in ICH. Camp-tomelic dysplasia is associated with hypoplasticfibulae, relative sparing of the upper limbs, andfrequent talipes equinovarus. These features arenot characteristic of ICH. OI and ICH may bedifferentiated due to the integrity of the spine,hands and feet, as well as the relative sparing of the

Table I—Severe prenatal cases of ICH

Reference Hydramnios Diagnosis/age Outcome

Jenkinson et al. (1943) +X-ray

26 weeksIntrauterine death; termination

27 weeks; length 36 cm

Barba and Frericks (1953) "X-ray

39 weeksLivebirth term 3600 g; slow resolution

of hyperostotic areas

Faul (1961) +At birth30 weeks’ gestation

Died 1st day from respiratory insufficiency;1860 g; length 41 cm

Scharer and Szabo (1966) +X-ray

38 weeksLivebirth 39 weeks; 1300 g; length 36 cm;almost complete resolution by 1 year

Labrune et al. (1983) +X-ray

25 weeksStillborn 25 weeks;2350 g; length 39 cm

Langer and Kaufman (1986) +X-ray

29 weeksDelivered 30 weeks; died 1st dayfrom respiratory insufficiency

Lecolier et al. (1992) +X-ray

23 weeks Terminated 23 weeks

Turnpenny et al. (1993) +U/S

24 weeks Delivered 27 weeks; died 1st day

Turnpenny et al. (1993) +U/S

28 weeks Stillborn 33 weeks; 2070 g

Turnpenny et al. (1993) +U/S

28 weeksLivebirth 37 weeks; 2930 g;resolution over 9 months

De Jong and Muller (1995) +U/S

29 weeks Stillborn 29 weeks; 1320 g

De Jong and Muller (1995) +U/S

30 weeksDelivered by C-section 33 weeks;

2100 g; died 1st day

Present case 1 +U/S

26 weeksDelivered 28 weeks;1000 g died day 10

Present case 2 "U/S

14 weeks Terminated 19 weeks

U/S=ultrasound.

775

? 1997 by John Wiley & Sons, Ltd. . ., . 17: 773–776

metaphyses, in ICH. Finally, ICH is generally notassociated with fractures, although fractures werenoted in case 2.Familial cases of ICH have most often been

reported with an autosomal dominant patternof inheritance, possibly with variable penetrance.The cases presented here appear to represent auto-somal recessive inheritance. Other potential expla-nations for the observed pedigree are subclinical orundiagnosed ICH in the patient or her husbandand parental germinal mosaicism.We have described two siblings with prenatally

diagnosed ICH in the absence of a family historyof the disorder. This report provides further evi-dence for heterogeneity and the existence of asevere autosomal recessive form of ICH. It is alsothe earliest reported prenatal diagnosis of thiscondition. This information will be useful in coun-selling patients at risk of an affected offspringdefining the phenotypic characteristics of severeprenatal ICH, and determining the genetic basisfor this disorder.

REFERENCES

Barba, W.P., Frericks, D.J. (1953). The familial occur-rence of infantile cortical hyperostosis in utero,J. Pediatr., 42, 141–150.

De Jong, G., Muller, L.M.M. (1995). Perinatal death intwo sibs with infantile cortical hyperostosis (Caffeydisease), Am. J. Med. Genet., 59, 134–138.

Faul, R. (1961). Familiares auftreten der infantilenkortikalen hyperostose. Arch. Kinderheilkd., 164, 271–276.

Jenkinson, E.L., Pfisterer, W.H., Latteier, K.K., Martin,M. (1943). A prenatal diagnosis of osteopetrosis,Am. J. Roentgenol., 49, 455–462.

Labrune, R., Guedj, G., Vial, M., Bessis, R., Roset, M.,Kerbrat, V. (1983). Maladie de Caffey a debut ante-natal, Arch. Fr. Pediatr., 40, 39–43.

Langer, R., Kaufman, H.J. (1986). Case report 363,Skeletal Radiol., 15, 377–382.

Lecolier, B., Bercau, G., Gonzales, M., Afriat, R.,Rambaud, D., Mulliez, N., De Kermadec, S. (1992).Radiographic, haematological, and biochemical find-ings in a fetus with Caffey disease, Prenat. Diagn., 12,637–641.

Saul, R.A., Lee, W.H., Stevenson, R.E. (1982). Caffey’sdisease revisited, Am. J. Dis. Child., 136, 56–60.

Scharer, K., Szabo, J. (1966). Familiare infantile corti-cale hyperostose mit pranatalem Beginn, Fortschr.Rontgenstr., 105, 154–163.

Turnpenny, P.D., Davidson, R., Stockdale, E.J.N.,Tolmie, J.L., Sutton, A.M. (1993). Clin. Dysmorph., 2,81–86.

776 . . .

. ., . 17: 773–776 (1997) ? 1997 by John Wiley & Sons, Ltd.