Central osteosclerosis with ectodermal dysplasia: clinical, laboratory, radiologic, and histopathologic characterization with review of the literature.

IBIDS is a syndrome characterized by ichthyosis, brittle hair, impaired intelligence, decreased fertility, and short stature, but unassociated with skeletal lesions. This condition is considered a form of trichothiodystrophy because hair from several cases has been found to have a low sulfur content. We describe a 9-year and 10-month-old white boy whose clinical features resemble the IBIDS syndrome (ichthyosis, brittle hair, cataracts, and short stature), but who also has marked axial osteosclerosis and peripheral osteopenia. No abnormalities of mineral homeostasis were noted. Histopathologic assessment of nondecalcified bone specimens excluded osteopetrosis, but suggested slow skeletal remodeling. When subjected to polarized light microscopy, his hair exhibited the band-like pattern of birefringence described in trichothiodystrophy. Literature review disclosed 8 patients, 2 of whom had been diagnosed as trichothiodystrophy, with like clinical features including osteosclerosis. These skeletal abnormalities together with clinical features of the IBIDS/trichiodystrophy syndrome, we believe, reflect the prototype of a disorder that seems best described as central osteosclerosis with ectodermal dysplasia.

Polycystic bone disease: A new, autosomal dominant disorder.

We describe a new heritable bone disease characterized radiographically by increasingly numerous and enlarging cyst-like lesions throughout the skeleton. Beginning in early childhood, a father, son, and daughter all suffered from progressively frequent pathological fractures involving such radiolucencies. Healing occurred uneventfully and with little residual pain or deformity. Biochemical parameters of mineral homeostasis and skeletal turnover were normal. Bone scanning showed increased radioisotope uptake primarily in fractures and in the largest collections of the lesions. The histopathology is uncertain, but may reflect a form of intraosseous lipomatosis. This unique condition, which we have provisionally named polycystic bone disease, is inherited as an autosomal dominant trait with a high degree of penetrance.

Pseudo-(tumor-induced) rickets.

An athletic 8-year-old boy developed severe muscle weakness over 2 years. At the age of 10 years, investigation for possible neuromuscular disease disclosed hypophosphatemia (1.8 mg/dl) and rickets. There was selective renal tubular wasting of inorganic phosphate (Pi) but no history of toxin exposure, familial bone or kidney disease, or biochemical evidence of vitamin D deficiency. Urine amino acid quantitation was unremarkable. Serum 1,25-dihydroxyvitamin D [1,25(OH)2D] concentration was in the lower half of the reference range. Our presumptive diagnosis was tumor-induced rickets; however, physical examination and bone scanning in search of a neoplasm were unrevealing. Soon after 1,25(OH)2D3 and Pi treatment began, muscle strength improved considerably. After 6 months of therapy, radiographic abnormalities were substantially better. During the next 6 years, physical examinations, a second bone scan, whole-body and nasal sinus magnetic resonance imaging, and octreotide scintigraphy were unremarkable. When his physes fused at the age of 16 years, assessment of his course showed excellent control of his rickets requiring decreasing doses of medication. Furthermore, fasting serum Pi levels and tubular maximum phosphorus/glomerular filtration (TmP/ GFR) values had increased steadily and normalized after 3 years of treatment. Accordingly, therapy was stopped. Seven months after stopping medication, he continues to feel completely well. Fasting serum Pi levels, TmP/GFR, other biochemical parameters of bone and mineral homeostasis, creatinine clearance, and renal sonography are normal. Neither spontaneous or pharmacologic cure of tumor-induced rickets or osteomalacia nor a patient matching ours has been reported. His disorder, which we call pseudo-(tumor-induced) rickets, should be considered when investigation for oncogenic rickets or osteomalacia discloses no causal lesion. Consequently, prolonged medical therapy and futile searches for a neoplasm may be avoided.

Preonset studies of spondyloepiphyseal dysplasia tarda caused by a novel 2-base pair deletion in SEDL encoding sedlin.

Spondyloepiphyseal dysplasia tarda (SEDT), an X-linked recessive skeletal disorder, presents with disproportionate short stature and "barrel-chest" deformity in affected (hemizygous) adolescent boys. In four reported families to date, mutations in a gene designated SEDL (spondyloepiphyseal dysplasia late) cosegregate with SEDT. We diagnosed SEDT in a short-stature, kyphotic 15-year-old boy because of his characteristic vertebral malformations. Clinical manifestations of SEDT were evident in at least four previous generations. A novel 2-base pair (bp) deletion in exon 5 of SEDL was found in the propositus by polymerase chain reaction (PCR) amplification and sequencing of all four coding exons. The mutation ATdel241-242 cosegregated with the kindred's skeletal disease. The deletion is adjacent to a noncanonical splice site for exon 5 but does not alter splicing. Instead, it deletes 2 bp from the coding sequence, causing a frameshift. A maternal aunt and her three young sons were investigated subsequently. Radiographs showed subtle shaping abnormalities of her pelvis and knees, suggesting heterozygosity. X-rays of the spine and pelvis of her 8-year-old son revealed characteristic changes of SEDT, but her younger sons (aged 6 years and 3 years) showed no abnormalities. SEDL analysis confirmed that she and only her eldest boy had the 2-bp deletion. Molecular testing of SEDL enables carrier detection and definitive diagnosis before clinical or radiographic expression of SEDT. Although there is no specific treatment for SEDT, preexpression molecular testing of SEDL could be helpful if avoiding physical activities potentially injurious to the spine and the joints proves beneficial.

Deficiency of the alpha-subunit of the stimulatory G protein and severe extraskeletal ossification.

Progressive osseous heteroplasia (POH) is a rare disorder characterized by dermal ossification beginning in infancy followed by increasing and extensive bone formation in deep muscle and fascia. We describe two unrelated girls with typical clinical, radiographic, and histological features of POH who also have findings of another uncommon heritable disorder, Albright hereditary osteodystrophy (AHO). One patient has mild brachydactyly but no endocrinopathy, whereas the other manifests brachydactyly, obesity, and target tissue resistance to thyrotropin and parathyroid hormone (PTH). Levels of the alpha-subunit of the G protein (Gsalpha) were reduced in erythrocyte membranes from both girls and a nonsense mutation (Q12X) in exon 1 of the GNAS1 gene was identified in genomic DNA from the mildly affected patient. Features of POH and AHO in two individuals suggest that these conditions share a similar molecular basis and pathogenesis and that isolated severe extraskeletal ossification may be another manifestation of Gsalpha deficiency.

Expansile skeletal hyperphosphatasia: a new familial metabolic bone disease.

We describe a new familial metabolic bone disease characterized by expanding hyperostotic long bones, early onset deafness, premature tooth loss, and episodic hypercalcemia. The condition affects a mother and daughter studied at the age of 36 years and 11 years, respectively. Both individuals lost all hearing in early childhood and suffered premature shedding of teeth. Skeletal pains began just before puberty. Swelling and aching of most middle phalanges in the hands is an especially troublesome manifestation. The mother also had episodes of symptomatic hypercalcemia first documented in late childhood and subsequently during intercurrent illness and postpartum lactation. Radiographs show hyperostosis and/or osteosclerosis predominantly in the skull and appendicular skeleton. Long bones also are expanded considerably, especially the middle phalanges in the fingers. The mother's skeletal abnormalities are more severe. Biochemical parameters of bone turnover, including serum alkaline phosphatase (ALP) activity, are elevated substantially. In the proposita, dynamic histomorphometry of nondecalcified sections of iliac crest revealed rapid skeletal remodeling. In the mother, who had been treated with bisphosphonates, electron microscopy (EM) showed disorganized collagen bundles as well as necrotic and apoptotic bone cells but no osteocytic osteolysis. Measles virus gene transcripts were not detected in peripheral blood monocytes. Karyotyping was normal, 46,XX. Hyperphosphatasia with bone disease previously has been reported as either a sporadic or autosomal recessive condition. Expansile skeletal hyperphosphatasia (ESH) is probably inherited as an autosomal dominant trait with a high degree of penetrance.

Juvenile Paget disease: life-long features of a mildly affected young woman.

Unusually mild Juvenile Paget Disease (JPD) was extensively investigated in a mentally retarded 21-year-old white woman. Progressive bowing deformitity of her lower limbs began at age 1 1/2 years. Nontraumatic fractures of both femora and both tibias occurred between ages 9 and 14 years. During adulthood, cortical thickening, osteosclerosis, and bowing affected these bones. Serum alkaline phosphatase (ALP) activity was persistently elevated. We found her serum osteocalcin and urinary hydroxyproline and pyridinoline/deoxypyridinoline to also be increased. The iliac crest histology, at ages 14 and 21 years, showed wide cortices and enhanced skeletal remodeling yet the bone was exclusively lamellar. Features of classic Paget Bone Disease (PBD)--such as hypermultinucleated osteoclasts, peritrabecular fibrosis, and mosaic or woven bone--were absent. Electron microscopy revealed no cytoplasmic or nuclear inclusions. Her dermal fibroblasts in culture synthesized unremarkable levels of ALP with proper membrane topography and lipid anchoring; ALP released into the medium also appeared normal. Six months of synthetic human calcitonin therapy daily appeared to reduce here lower limb pain and warmth, but the radiographs, biochemical parameters of skeletal turnover, and bone scintigraphy were unaltered. Lamellar bone has been reported in JPD but accompanied by excessive amounts of woven bone. Our patient reveals that lamellar bone without features of PBD can characterize the skeletal histopathology of the especially rare case of mild JPD.

Decreased cortical thickness & osteopenia in children with diabetes mellitus.

A recent study using the photon absorption technique has revealed a high frequency of significant bone loss in diabetic adults regardless of age or duration of diabetes. In this study 107 diabetic children age 4-18 were studied using cortical bone thickness and skeletal maturation as indicators of bone development. Overall, 25% of all diabetic children had cortical thickness values below the five percent limit for normal children. This was more common in boys than girls and was unrelated to duration of diabetes. A modest increase in delayed skeletal maturation did not account for the cortical thinning and osteopenia observed. The cause of the osteopenia of diabetic children remains an enigma.

Spondyloepimetaphyseal dysplasia: clinical and radiologic investigation of a large kindred manifesting autosomal dominant inheritance, and a review of the literature.

Spondyloepimetaphyseal dysplasias (SEMDs) are a heterogeneous group of skeletal disorders that can have a genetic basis, but their classification and prognostication suffer because few families have been extensively studied. We describe a large kindred affected by a unique type of SEMD that is transmitted as an autosomal dominant trait. The propositus and his affected brother and first cousin were evaluated as inpatients. Other kindred members were screened by telephone interviews and lateral thoraco-lumbar spine radiographs, and then, in most cases, investigated by additional x-ray studies. Of the 29 living members of the kindred, 22 were studied radiologically. Among the 22 subjects investigated, 15 were affected, and the status of 1 individual with minor changes on x-ray was indeterminate. The deceased patriarch was presumed to be affected. These 16 affected subjects could usually, but not invariably, be distinguished from their unaffected sex-matched siblings by their smaller heights. Nevertheless, it was only affected children who had short stature; the heights of all affected adults were normal. Often, affected individuals had rhizomelic shortening, especially of the lower extremities, and genu varum (not always evident clinically, but present on radiographs). Occasionally, they also manifested limited extension of their upper limbs. Radiologic study showed abnormal metaphyses, epiphyses, and vertebrae in affected children, but these 3 skeletal regions became less remarkable by late childhood and most affected adults had normal epiphyses. One obligate affected man had only spinal changes. Despite their normal heights, severely affected adults who had bowing deformity of their legs developed disabling degenerative joint disease limited to the knees in the 7th decade of life--disease severe enough to require knee replacement surgery.

X-linked recessive spondyloepiphyseal dysplasia tarda. Clinical and radiographic evolution in a 6-generation kindred and review of the literature.

We characterize the clinical and radiographic evolution of X-linked recessive spondyloepiphyseal dysplasia tarda (SEDT) in a 6-generation kindred from Arkansas (SEDT(AK)). Our observations show the natural progression of SEDT(AK) and enable carrier detection by radiographic study. We find that, SEDT(AK) manifests as a postnatal defect. Affected hemizygous males can have radiographically normal vertebrae at birth. The pathogenesis seems to involve a developmental disturbance in endochondral bone formation that is reflected most dramatically in vertebrae by a radiographically inapparent ring apophysis. This defect leads to distinctive malformation of the anterior margins of the lumbar vertebrae during childhood. Subsequently, there is degeneration of intervertebral discs and destruction of spinal facet joints. In the femur, the head, neck, and distal condyles are abnormally shaped and become distorted so that osteoarthritis of the hip is not uncommon. Obligate carrier females heterozygous for the SEDT(AK) gene defect demonstrate several similar but more subtle skeletal abnormalities beginning in early adult life. These women seem to be troubled frequently by arthralgia by middle age. The cumulative findings in SEDT(AK) implicate a defect in a gene at Xp22.2-22.1 that engenders a relatively mild disturbance in endochondral bone formation, especially in the axial skeleton. Accounts of large, well-characterized SEDT kindreds remain essential to appreciate fully any interfamily variability of disease expression and to understand better the pathogenesis of the SEDT defect on the X chromosome.

Hypercalciuria in osteogenesis imperfecta: a follow-up study to assess renal effects.

In 1991, we reported that hypercalciuria is a common finding in our pediatric patient population with osteogenesis imperfecta (OI) (17 of 47 = 36%). Here, we prospectively screened 12 of these hypercalciuric children, on average 4 years subsequent to the discovery of elevated urine calcium levels, for adverse effects on renal function. Despite an ad libitum decrease since initial investigation of about 30% in their previously normal dietary calcium intake (adjusted for body weight), 8 of the 12 patients remained hypercalciuric (urine calcium/creatinine > 0.62 mmol/mmol). We found, once again, that urinary calcium levels significantly correlated with the severity of the skeletal disease as assessed by z-score for height (r = -0.75, p = 0.005). Evaluation of kidney function, however, revealed: (i) normal routine urinalysis in all but 1 subject who had transient microscopic hematuria; (ii) unremarkable concentrating ability determined by fasting urine osmolality; (iii) normal creatinine clearance, and (iv) unremarkable ultrasonography to measure renal size and to screen for nephrocalcinosis or nephrolithiasis. Although no significant renal compromise was detected with these studies in our hypercalciuric pediatric OI patients, investigation of affected adults, especially those severely affected, will be important to assess whether this is a long-term problem and if adverse effects on the kidneys do develop.

Intermittent radiographic changes of rickets without defective trabecular bone mineralization in a case of spondylometaphyseal dysplasia.

Although a variety of metaphyseal and spondylometaphyseal dysplasias have been identified, the natural course of the skeletal defects in these disorders has not been well characterized. We describe an 8-year-old girl with spondylometaphyseal dysplasia, most closely resembling the Kozlowski type, in whom rachitic metaphyseal involvement underwent dramatic radiographic healing when she wore leg braces; discontinuation of the braces was followed by recurrence of the growth plate abnormalities. A generalized disturbance in mineral metabolism or skeletal remodeling to explain these radiographic changes was excluded by extensive biochemical studies and histologic examination of an undecalcified iliac crest specimen. Our observations suggest that the defect in endochondral bone formation in the spondylometaphyseal dysplasias may be responsive to mechanical factors and that interventions that alter stress and strain on the skeleton, such as immobilization or use of orthopedic braces, may considerably modify the radiographic appearance of the growth plate disturbance.

X-linked hypophosphatemia: normal renal function despite medullary nephrocalcinosis 25 years after transient vitamin D2-induced renal azotemia.

Nephrocalcinosis (NC) detected by ultrasound is a recognized abnormality for some patients with X-linked hypophosphatemia (XLH) who received vitamin D2 and inorganic phosphate therapy, but is commonly observed in XLH patients treated with 1,25-dihydroxyvitamin D3 and inorganic phosphate supplementation. Nevertheless, long-term follow-up of kidney function in XLH patients with NC detected ultrasonographically has not been reported. We investigated two women with XLH, ages 31 (patient 1) and 39 (patient 2) years, each of whom had suffered at least one documented episode of vitamin D2-induced hypercalcemia and renal azotemia during childhood. Patient 2 had also been treated with inorganic phosphate. No medications for XLH had been taken during adulthood. Renal ultrasonography at our institution demonstrated marked bilateral medullary NC in both women. No other explanation was found for their NC that apparently occurred several decades earlier from medical therapy for XLH. Detailed studies (including creatinine clearance, beta2-microglobulin excretion, and fasting urinary osmolality and acidification) revealed no impairment of kidney function in either patient. Our findings indicate that subradiographic medullary NC acquired during medical therapy for XLH may persist for decades, but with no adverse renal sequelae. Definitive (long-term) assessment of kidney function in the XLH population with NC, however, will be necessary to fully understand the risk of current medical treatment for this most common heritable form of rickets.

Osteopetrosis, renal tubular acidosis and basal ganglia calcification in three sisters.

Three adult sisters with osteopetrosis in infancy had spontaneous resolution of bone modeling defects and osteosclerosis. During adolescence, basal ganglia calcification developed in two. Renal tubular acidosis (type I) was diagnosed in each during early adulthood. The disorder was transmitted apparently as a recessive trait--the same mode of inheritance as for the "malignant" form of osteopetrosis which is usually fatal during childhood. Electron microscopy of bone suggested that osteoclasts failed to form "ruffled membranes" characteristic of active bone resorbing cells. Chronic systemic acidosis may have ameliorated the skeletal manifestations of this new syndrome.

Intracerebellar hemorrhage in a premature newborn: diagnosis by real-time ultrasound and correlation with autopsy findings.

The identification of intracerebellar hemorrhage in a living premature infant by real-time ultrasound scan and confirmation of the findings at autopsy are described. This represents the first demonstration of the value of this noninvasive, convenient, and safe means of brain imaging in diagnosis of this lesion. Previous studies have described the role of the computed tomography (CT) scan in identification of intracerebellar hemorrhage in the newborn. Because infants with intracerebellar hemorrhage are usually critically ill, a means of identification of the lesion that could be utilized at the bedside rather than an approach that requires transport to a CT scanner is needed. This study indicates that portable real-time ultrasound scanning can satisfy that need.

Hypotrichosis with spondyloepimetaphyseal dysplasia in three generations: a new autosomal dominant syndrome.

We describe a family with a new disorder characterized by congenital hypotrichosis and spondyloepimetaphyseal dysplasia that results in mild rhizomelic short stature. Five individuals in 3 generations are affected with autosomal dominant inheritance.

Bilateral radial ray hypoplasia with multiple epiphyseal dysplasia.

We describe a 5-4/12-year-old girl with the unique combination of bilateral radial ray hypoplasia and multiple epiphyseal dysplasia (MED). Radial ray hypoplasia was diagnosed at birth. MED was documented at age 4-3/12 years when she presented with leg pain and short stature and was found to have femoral anteversion and tibial torsion giving rise to severe genu valgum deformity and intoeing. She has no facial anomalies and is developmentally normal. Family history is unremarkable and chromosomal analysis was normal. Investigation of mineral metabolism showed idiopathic hypercalciuria. Surgical lengthening of her severely hypoplastic left radius at age 19 months was successful. Bilateral femoral and tibial osteotomies at age 5-4/12 years corrected her lower limb deformities. This combination of two distinctive but rare skeletal abnormalities may represent a new syndrome.

Combined deficiency of beta-galactosidase and neuraminidase: natural history of the disease in the first 18 years of an American patient with late infantile onset form.

We describe the clinical findings over the first 18 years of a patient with a novel phenotype for galactosialidosis, the storage disease produced by the combined deficiency of beta-galactosidase and neuraminidase. Clinical findings in the first few months included somewhat unusual appearance and hepatosplenomegaly. Dysostosis multiplex was evident by age 2 1/2 years. Mitral and aortic valvular disease appeared over the next few years and cardiac disease has become the most important clinical problem. Foam cells were present in the bone marrow, and vacuolated lymphocytes were present in the peripheral blood smear. The patient had no neurological symptoms, cherry red spots, or intellectual deterioration during the first 18 years. Evidence presented elsewhere indicates that the basic defect in this late infantile form of galactosialidosis (as is thought to be true for the other forms of galactosialidosis) is a reduced amount of the 32 kDa phosphoglycoprotein which associates with beta-galactosidase and alpha-neuraminidase in lysosomes.

Imaging of sinusitis in children.

In most cases, sinusitis remains a clinical diagnosis. Imaging studies can be useful in diagnosing patients with atypical presentations, but plain radiographs lack sensitivity and specificity, and coronal sinus CT lacks specificity. Coronal sinus CT is generally used when complications of sinusitis are suspected or when sinus surgery is considered.

Binary nature and radiographic identifiability of craniosynostosis.

RATIONALE AND OBJECTIVES: Two independent gold standards and diagnoses from three-dimensional computed tomography (CT) images were used to examine the possibility that craniosynostosis is a binary abnormality that potentially may be diagnosed without error. METHODS: Surgical reports, histology of excised sutures, and three-dimensional CT images were compared for 25 children undergoing surgical management of craniosynostosis. Surgical reports identified sutures as normal or abnormal. Histology reported suture closure on a 5-point scale. Four radiologists used three-dimensional CT images to diagnose sutures on a 6-point rated response scale. RESULTS: Sutures with histology 0, 1, or 2 were normal on surgical reports, and those with histology 3 or 4 were abnormal. Most readers achieved nearly perfect sensitivity and specificity. Reader confidence was unrelated to degree of pathology. CONCLUSION: Craniosynostosis appears to be binary in our sample. Surgical reports, pathology results, and three-dimensional CT images read by experienced viewers achieved nearly perfect agreement.