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Prenatal Caffey Disease Ori Hochwald MD and Horacio Osiovich MD FRCP

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Prenatal Caffey Disease Ori Hochwald MD and Horacio Osiovich MD FRCP IMAJ • VOL 13 • FEBRUARY 2011 CASE COMMUNICATIONS Prenatal Caffey Disease Ori Hochwald MD and Horacio Osiovich MD FRCP Division of Neonatology, Department of Pediatrics, Children’s & Women’s Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada fetal hydrops. This is a rare disorder with diagnosis was found at that point. A KEY WORDS: Caffey disease, cortical hyperostosis, a high mortality rate due to prematurity decompression amniocentesis was per- hydrops, polyhydramnios, and lung hypoplasia [3]. We report a case formed at 28 weeks 5 days gestation due prematurity, pulmonary hypoplasia of prenatal Caffey disease that presented to an increased amount of amniotic fluid. IMAJ 2011; 13: 113–114 prenatally with polyhydramnios, fetal Labor began soon after the procedure. hydrops and hepatomegaly followed by The infant girl was born by spontan- prematurity and pulmonary hypoplasia; eous vaginal delivery. She was depressed the diagnosis was based on the abnormal and apneic at birth, was intubated in the wo forms of cortical hyperostosis skeletal appearance in the initial chest delivery room and received bovine sur- T or Caffey disease (OMIM *114000) X-ray. factant. Initial physical examination was have been described: prenatal and infan- remarkable for generalized edema, mild tile. The classical mild infantile form was ascites, hepatomegaly and a bent and described by Roske in 1930 and further PATIENT DESCRIPTION bruised left arm. A chest X-ray showed characterized by Caffey and Silverman Our patient was born at 28 weeks 5 days moderate hyaline membrane disease and in 1945. It is characterized by a massive gestation with a birth weight of 1455 g, an exuberant periosteal reaction involv- subperiosteal new bone formation that head circumference 27.5 cm and length ing the humeral diaphyses and the ribs typically involves the diaphyses of long 40 cm. Her mother was a healthy 38 [Figure A]. Skeletal X-rays demonstrated bones, mandible and clavicles [1]. In addi- year old, gravida 4, para 1. The mother an extensive symmetrical involvement tion, painful swelling of soft tissues, irri- had received good prenatal care and the of other bones, including the femurs tability and fever are quite common. The ultrasound scans performed at 11 and [Figure B] and the mandible [Figure C]. time of onset is usually within the first 6 19 weeks were normal. She was immune The periosteal reaction seen in the X-rays months of life with resolution before age to rubella, and serology was negative for is consistent with prenatal-onset infantile 2 years. The clinical course is variable and hepatitis B, human immunodeficiency cortical hyperostosis, also known as pre- unpredictable [2]. The prenatal form of virus and syphilis. Pregnancy was unre- natal Caffey disease. Caffey disease has a more severe course markable until 27 weeks gestation when Investigations for possible causes characterized by extensive hyperostotic an ultrasound scan showed polyhydram- of hydrops fetalis in our patient were bone involvement, angulations and short- nios and fetal hydrops, moderate ascites negative. These included white blood cell ening of long bones, polyhydramnios, and and hepatomegaly. No specific prenatal count, hemoglobin and platelet count, [A] Lung appearance consistent with hyaline membrane disease. There was an [C] Periosteal reaction involving the mandible. [D] X-rays of both upper limbs at 3 exuberant periosteal reaction involving the humeral diaphyses and the ribs. months of age: There is evidence of bony remodeling and increased osseous definition [B] Periosteal reaction involving the entire length of the femoral diaphysis. seen at the humeral, ulnar and radial diaphyses. No periosteal reaction is noted. 113 CASE COMMUNICATIONS IMAJ • VOL 13 • FEBRUARY 2011 heart anatomy on echocardiogram, oph- portal areas might also compress the ter- Caffey disease can be sporadic or thalmological examination, serology for minal portal venules, resulting in pre- transmitted as an autosomal dominant congenital infections (TORCH, syphilis sinusoidal portal hypertension leading to disorder with variable penetrance (OMIM and parvovirus), and metabolic screen for anasarca and hydrops that may also con- #114000). Affected members of some urine organic acids, serum amino acids, tribute to the development of pulmonary families with Caffey disease were found storage disease (mucopolysaccharides, hypoplasia [5]. to be heterozygous for a missense muta- oligosaccharides) and hexosaminidase. Schweiger et al. [1] reviewed 44 rep- tion (3040 C→T) in exon 41 of the gene Her course in the neonatal intensive orted cases of Caffey disease with ante- encoding the α1 chain of type I collagen care unit was complicated by hyaline natal onset, identifying severe and mild (COL1A1), altering residue 836 (R836C) membrane disease and persistent pulmo- forms of the condition. Severe prenatal in the triple-helical domain of this chain nary hypertension. She was ventilated for cortical hyperostosis was present in 26 [2,4]. This mutation was found in cases 5 weeks, followed by continuous positive patients: 11 were stillborn, of whom of the infantile as well as prenatal form of airway pressure, with supplemental oxy- 6 had pulmonary hypoplasia; 15 were this disease. The COL1A1 gene is respon- gen and diuretic therapy for an additional liveborn, 6 of whom died in the neona- sible for other collagen diseases such as 3 months. She had conjugated hyperbiliru- tal period due to respiratory problems. osteogenesis imperfecta and Ehlers- binemia, with normal liver enzymes from Polyhydramnios was the first presenting Danlos syndrome [2]. In other familial the first day of life, treated with ursodiol manifestation in most of these pregnan- cases, autosomal recessive inheritance has and resolving after several weeks. She was cies. Additional findings included fetal been suggested [2]. treated with supplementation of vitamin hydrops or skin edema (50% of cases) D, calcium and phosphate. The periosteal and hepatosplenomegaly (31% of cases). Acknowledgment: reaction resolved completely before dis- In all survivors, a remarkable resolution The authors thank Dr. M. Whitfield for his charge at age 3.5 months [Figure D]. of hyperostosis was observed after several helpful suggestions in the writing of the manuscript. weeks. Eighteen patients, classified as having the mild form, were born at term, COMMENT Corresponding author: and fetal hydrops, hepatomegaly or bone Dr. H. Osiovich Histological analysis of cortical areas in abnormalities were not detected before Neonatal Intensive Care Unit, BC’s Children’s Caffey disease reveals abnormal deposi- the 35th week of gestation [1]. Hospital, 4480 Oak Street, Vancouver, BC V6H 3V4, Canada tion of hyperplastic, immature lamellar The prenatal diagnosis of prenatal email: [email protected] bone that replaces the original cortical Caffey disease is based on ultrasound bone. Additional findings include thick- findings (as early as 14 weeks of gesta- References ening of the periosteum, intense prolif- tion, average 27 weeks) of short and 1. Schweiger S, Chaoui R, Tennstedt C, Lehmann K, eration of subperiosteal cells and fibrosis angulated bones with irregular diaphyses Mundlos S, Tinschert S. Antenatal onset of cortical of bone marrow [4]. Collectively, these and increased echogenicity and, typically, hyperostosis (Caffey disease): case report and review. Am J Med Genet A 2003; 120A (4): 547-52. findings suggest a common pathway of an the absence of fractures. The differential 2. Gensure RC, Makitie O, Barclay C, et al. A novel inflammatory reaction [5]. The appear- diagnosis of prenatal Caffey disease COL1A1 mutation in infantile cortical hyperostosis ance of this process early in gestation includes hypophosphatasia and camp- (Caffey disease) expands the spectrum of collagen- related disorders. J Clin Invest 2005; 115 (5): 1250-7. may explain the lethality of prenatal-onset tomelic dysplasia, both of which can pres- 3. Lecolier B, Bercau G, Gonzales M, et al. Radio- Caffey disease. The fibrotic bone marrow ent bowing and angulation of long bones, graphic, haematological, and biochemical findings generates hepatic myeloid extramedulary and osteogenesis imperfecta type 2, usu- in a fetus with Caffey disease. Prenat Diagn 1992; 12 (8): 637-41. hematopoiesis that leads to significant ally associated with fractures. Congenital 4. Glorieux FH. Caffey disease: an unlikely collagen- hepatomegaly which, combined with a syphilis can present with periosteal new opathy. J Clin Invest 2005; 115 (5): 1142-4. small thoracic cavity due to the widened bone formation [3]. Three-dimensional 5. Wright JR, Jr., Van den Hof MC, Macken MB. ribs, results in the development of hyp- computed tomography may be useful in Prenatal infantile cortical hyperostosis (Caffey's disease): a 'hepatic myeloid hyperplasia-pulmonary oplastic lungs. Furthermore, exuberant the prenatal diagnosis of lethal infantile hypoplasia sequence' can explain the lethality of early extramedulary hematopoiesis in the peri- cortical hyperostosis. onset cases. Prenat Diagn 2005; 25 (10): 939-44. “The television, that insidious beast, that Medusa which freezes a billion people to stone every night, staring fixedly, thatS iren which called and sang and promised so much and gave, after all, so little” Ray Bradbury (born 1920), American fantasy, horror, science fiction and mystery writer, many of whose works have been adapted into television shows or films 114 .
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