Schimke immuno-osseous dysplasia: A newly recognized multisystem disease

Schimke immuno-osseous dysplasia: A newly recognized multisystem disease J. Spranger, MD, G. K. Hinkel, MD, H. StOss, MD, W. Thoenes, MD, D. Wargowski, MD, a n d F. Zepp, MD From the Children's Hospital and Department of Pathology, University of Mainz; Children's Hospital, Medical Academy, Dresden; Department of Pathology, University of Erlangen, Germany; and the Clinical Genetics Center, Madison, Wisconsin

On the basis of five cases personally observed and one previously reported, we describe a disorder characterized by skeletal dysplasia, rapidly progressive nephropathy, episodes of lymphopenia, and pigmentary skin changes. Defects of T-cell function were compatible with an autoimmune process. The disorder is probably of genetic origin and inherited as an autosomal recessive trait. (J PEDIATR1991;119:64-72)

Inborn errors of bone development are sometimes associated with dysplastic changes of other organs such as the kidneys, intestine, or i m m u n e system. 13 In 1974 Schimke et al. 4 described a 6-year-old girl with spondyloepiphyseal dysplasia, progressive renal disease, lymphopenia, and signs of defective cellular immunity; they found increased amounts of urinary chondroitin 6-sulfate and classified the disorder as a new mucopolysaccharidosis. W e observed five patients with a n identical clinical and skeletal phenotype and with similar laboratory changes but without mucopolysacchariduria; we delineate the charac-

Clinical examination of the patient at 5 years of age showed a short-trunk type of dwarfism with a height of 80 cm and head circumference of 46 cm (both < 3rd percentiles), short neck, accentuated lumbar lordosis, and prominent hips as a result of bilateral hip dislocation. The patient had a peculiar face with a broad, depressed nasal bridge, bulbous tip of the nose, and slightly elongated upper lip. The hair was thin, and periorbital edema was present. The girl's voice was high pitched. Numerous pigmented spots resembling lentigines were present on the abdomen. Radiographs showed spondyloepiphyseal dysplasia (Fig. 1, A and C, and Fig. 2, A). Abnormal laboratory values included massive proteinuria with occasional erythrocytes, lymphopenia (leuko-

teristics of this new multisystem disorder, which we propose to n a m e Schimke immuno-osseous dysplasia. CASE REPORTS Case 1. A 5-year-old girl was seen for evaluation of short stature and proteinuria. Her parents were healthy and nonconsanguineous. A younger brother was similarly affected (case 2). The girl was born at term with a weight of 13 gm and a length of 39 cm. The placenta was small and thin with fibrotic changes. Early development was unremarkable. The child was immunized against tuberculosis and smallpox, without undue reactions. At 18 months, delayed growth was noticed. When she was 3~A years of age, operative correction of bilaterally dislocated hips was planned; proteinuria and hypertension were identified. Generalized edema and ascites appeared, and a diagnosis of nephrosis was made. The patient had recurrent upper respiratory tract infections, diarrhea, and Candida dermatitis. Submitted for publication Oct. 2, 1990; accepted Jan. 16, 1991. Reprint requests: J. Spranger, MD, University Kinderklinik, Langenbeekstr. 1 D-65 Mainz, Germany.

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cyte count 4200 cells/tzl, l 5% lymphocytes), and low serum protein level (46 gm/L) with a low 3~-globulin fraction. Immunoglobulin levels were as follows: IgG, 472 mg/dl; IgA, 138 mg/dl; and IgM,261 mg/dt. Levels of total complement and components CI through C4 were normal. During the next 3 years, progressive signs of renal insufficiency developed. Serum cholesterol level rose to 915 mg/dl (2366 p.mol/L). Steroid and immunosuppressive therapy was unsuccessful, and the child died at 8 years of age of renal failure. Autopsy showed small kidneys, residua of earlier left renal vein thrombosis, and marked arteriosclerotic changes in the aorta, carotid, and coronary arteries. Case 2. The younger brother of patient i was born at term with a weight of 2100 gm, a length of 45 cm, and head circumference of 32 cm. His course was similar to that of his sister, with retarded growth at 21/2years, first signs of renal disease at about 3 years, and progressive renal insufficiency, hypertension, and death from renal

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Immuno-osseous dysplasia

Fig. t. A, Case 1 when patient was 2 years of age. B, Case 4 when patient was 3Vz years of age. was 6 years of age. At all ages vertebral bodies are ovoid and dorsally flattened.

failure at 8 years of age. The hips were not dislocated, and he did not have frequent infections or diarrhea. Clinical examination at 5 years showed almost identical findings to those in the boy's sister; height was 86 cm, weight 12 kg, and head circumference 48 cm. He had the same body proportions, facial appearance, high-pitched voice, and pigmentary skin changes (Fig. 3, A). Radiographs showed spondyloepiphyseal dysplasia. Proteinuria, low serum protein levels, low serum IgG, and lymphopenia with counts between 50 and 1200 cells/~l were present. Urinary mucopolysaccharide levels were normal. Renal insufficiency and hypertension developed, and the patient died of renal failure at 8 years

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C, Case 1 when patient

of age. Autopsy showed small kidneys and distinct arteriosclerotic lesions in the major arteries. Case 3. A 9-year-old boy, the only child of nonconsanguineous parents, was seen for evaluation of his small stature. (He is patient 1 of Ehrich et al. 5) He was delivered by cesarean section at 34 weeks of gestational age because of placental insufficiency. He remained short but was otherwise normal until the age of 4 years, when gross edema appeared and a nephrotic syndrome was diagnosed. At the age of 5 years kidney transplantation was performed because of rapidly progressive renal failure. Posttransplantation treatment consisted of cyclosporine and low doses of prednisolone. Renal function remained normal, but growth failure persisted, with a

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The Journal of Pediatrics July 1991

Fig. 2. A, Patient I at 3 years of age B, Patient 3 at 9 years of age. Ilia are small because of hypoplasia of lower portions. Acetabular roofs are slanted with wide lilac angles. Capital femoral epiphyses are small. Femoral heads are laterally disptaced with small epiphyses and dislocated in Case I0 C, Case 4, when patient was 4 years of age. In this case, ilia are small but acetabula are well developed with small lilac angles. Proximal femoral epiphyses are well ossified but not entirely covered by acetabula. Coxa valga is present in all cases. slowly increasing height deficit. Signs of focal cerebral ischemia first occurred when the patient was 12 years of age. Physical examination showed a length of 101 cm (