PEDIATRICS Vol. 118 No. 5 November 2006, pp. e1485-e1492 (doi:10.1542/peds.2006-0824)
ARTICLE |
Systemic Hyalinosis: A Distinctive Early Childhood–Onset Disorder Characterized by Mutations in the Anthrax Toxin Receptor 2 Gene (ANTRX2)
a Divisions of Medical Genetics
b Rheumatology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California
c Division of Medical Genetics, Department of Pediatrics, University of California, San Francisco, California
d Departments of Human Genetics
e Pediatrics
f Oncological Sciences, Mount Sinai School of Medicine, New York, New York
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ABSTRACT |
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 TOP ABSTRACT CLINICAL CASESRESULTS OF GENETIC TESTINGDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. We sought to further characterize the phenotype and facilitate clinical recognition of systemic hyalinosis in children who present with chronic pain and progressive contractures in early childhood.
PATIENTS AND METHODS. We report on 3 children who presented in infancy with symptoms and signs that initially were not recognized to be those of systemic hyalinosis. Although the children were evaluated for a variety of problems, including lysosomal storage disorders and nonaccidental trauma, all eventually underwent genetic analysis of the anthrax toxin receptor 2 gene (ANTRX2) and were diagnosed as having systemic hyalinosis.
RESULTS. We describe the recognizable but variable clinical phenotype of systemic hyalinosis and associated mutations in ANTRX2. Affected individuals presented in early infancy with severe pain and progressive contractures. Initial diagnostic evaluations were unrevealing; however, hyperpigmented skin over bony prominences, skin nodules, and fleshy perianal masses suggested a diagnosis of systemic hyalinosis. ANTRX2 analysis confirmed the diagnosis in each case. Although 2 of the children died in infancy as a result of complications of chronic diarrhea, the third child has survived into midchildhood. These data suggest that some ANTRX2 mutations, such as that identified in the long-term survivor, may be associated with a less severe course of disease.
CONCLUSIONS. Although some aspects of systemic hyalinosis may resemble lysosomal storage disorders, the clinical features of systemic hyalinosis are distinctive, and detection of an ANTRX2 mutation can confirm the diagnosis. Early recognition of affected individuals should allow for aggressive pain control and expectant management of the multiple associated problems, including gastrointestinal dysfunction.
Key Words: hyalinosis • chronic pain • progressive childhood contractures • gingival hypertrophy • anthrax toxin receptor 2 gene • genetic testing • fibromatosis
Abbreviations: ANTRX2—anthrax toxin receptor 2 gene
Systemic hyalinosis1–3 comprises an uncommon autosomal recessive disorder that presents in early childhood and is characterized by progressive joint contractures, skin papules and nodules, and severe chronic pain. Certain clinical features of this condition, such as coarse-appearing facial features, gingival hyperplasia, and progressive contractures, may resemble those of lysosomal storage disorders4; thus, recognition of systemic hyalinosis may be delayed. Recently, mutations in the anthrax toxin receptor 2 gene (ANTRX2, also known as the capillary morphogenesis protein 2 [CMG2] gene) were found to be the cause of systemic hyalinosis,5,6 whether the case was severe (infantile systemic hyalinosis, Online Mendelian Inheritance in Man [OMIM] No. 236490) or mild (juvenile hyaline fibromatosis, OMIM No. 228600). Early recognition of affected individuals is important, given the severe pain, associated disability, and potential for early childhood mortality.
Our purpose for this article was to further delineate the clinical spectrum of systemic hyalinosis by presenting 3 children with systemic hyalinosis who differ in disease severity and demonstrate features previously undescribed for this condition. We identify causative mutations in ANTRX2, including a previously undescribed mutation in an individual with relatively mild disease. We also propose management guidelines for care of children with this rare childhood disorder characterized by chronic pain and progressive joint contractures.
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CLINICAL CASES |
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TOPABSTRACTCLINICAL CASESRESULTS OF GENETIC TESTINGDISCUSSIONCONCLUSIONSREFERENCES |
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Patient 1
A Mexican American girl was born at term to nonconsanguineous parents. There was a healthy older sibling, and the family history was negative for birth defects, mental retardation, or genetic disorders. Her mother noticed decreased fetal movement during pregnancy. A prenatal ultrasound examination at 21 weeks' gestation demonstrated fetal pleural effusions, which resolved on subsequent scans. Her birth weight was 3065 g (25th–50th percentile), length was 47 cm (25th percentile), and head circumference was 33 cm (25th–50th percentile). The child had large-appearing ears. She was admitted to the NICU for observation and workup for a possible malformation syndrome. An echocardiogram and brain MRI were unremarkable. The patient was stable and discharged after 1 week; however, her mother noted that the child developed increasingly limited movement of her extremities over time. When the child was 1 to 2 months of age, she cried whenever she was handled, and she displayed significant contractures of both her large and small joints. A radiographic skeletal survey at 3 months of age revealed periosteal reaction of the femurs and humeri bilaterally and a left hip dislocation. Results of laboratory studies (plasma lactate, ammonia, amino acids, very-long-chain fatty acids, acylcarnitine profile, and urine organic acids) performed to assess a potential inborn error of metabolism were normal. The results of studies screening for a congenital disorder of glycosylation and a chromosome analysis were normal, as was the ophthalmology examination, including examination of the retina. She was referred to the pediatric rheumatology service and, subsequently, to genetics for additional evaluation.
At 6 months of age, the patient underwent an initial genetics evaluation and several follow-up examinations. Failure to thrive was diagnosed, with a weight of 5.9 kg (5th percentile) at 6 months of age and a weight of 6.8 kg (<5th percentile or 50th percentile for 5 months of age) at 11 months. Her head circumference, however, was spared (25th–50th percentile at 6 months of age and 25th percentile at 11 months of age). The patient (Fig 1A) was exquisitely sensitive to passive movement of her extremities, and she cried excessively. She had large ears (length: 5.8 and 4.8 cm at 7 months of age; >97th percentile) (Fig 1 B and C). The right ear had a simple helix, and fleshy preauricular nodules were present bilaterally that were irregular and not pedunculated. She had a slightly coarse facial appearance (Fig 1C) and a depressed nasal bridge. The gingiva were prominent. At 6 months of age, the liver edge was palpable 6 to 7 cm below the costal margin, and there were marked joint contractures of all 4 extremities that involved both the large and small joints (Fig 1D). The wrists, hands, and feet were swollen in appearance. The wrists were held in extension with the fingers flexed at the proximal and distal interphalangeal joints, resulting in a claw-hand appearance. The skin demonstrated hyperpigmented patches over bony prominences, including the wrists, elbows, spine, and malleoli of the ankles (Fig 1 E and F), and she was diaphoretic. A papule at the angle of her mouth (Fig 1C) and multiple pearly papules over the back of her neck (Fig 1B) and face were evident at 11 months of age. A fleshy perianal mass was also noted (Fig 1G). At 11 months of age, she could speak 3 words but could not roll or sit because of her contractures. She attempted to pick up objects, but her activity was limited by hand contractures.
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Results of enzymatic tests for lysosomal storage diseases, including mucolipidosis type II, were normal. A skin biopsy at 7 months of age was read as normal, but systemic hyalinosis was suspected on the basis of the distinctive clinical picture. Analysis for ANTRX2 mutations confirmed the diagnosis of systemic hyalinosis. The disease and its inheritance pattern were discussed with the family.
A palliative care team and pain management team were involved. The child was fed nasogastrically because of pain with feeding; however, weight gain was suboptimal. Scheduled pain medications were administered, including opioids and nonsteroidal antiinflammatory medication. Gabapentin was added in an additional attempt to alleviate pain, and the mother reported some subjective improvement in pain control. The patient was hospitalized twice for respiratory infections and was treated with antibiotics with resolution of symptoms. The pain persisted, and her contractures progressively worsened. She was treated with penicillamine, but her condition did not improve. At 13 months of age, she developed chronic diarrhea and protein-losing enteropathy, resulting in extensive edema, and she died.
Patient 2
A Mexican American boy was born at 40 weeks' gestation to parents who were second cousins. The mother had a history of 2 previous miscarriages. There were 2 older siblings, and the family history was negative for birth defects, mental retardation, or genetic disorders. Prenatal history was unremarkable. At birth, his weight was 2885 g (25th percentile), length was 49.5 cm (50th–75th percentile), and head circumference was 33 cm (25th–50th percentile). His mother reported that he exhibited significantly decreased movement since birth, accompanied by marked pain. He was referred to an orthopedic surgeon at 2 weeks of age. Radiographs demonstrated periosteal reaction of the humerus and ulna, which prompted concern for fractures associated with nonaccidental trauma. Results of a head computed tomography scan and an ophthalmology examination were normal, and an evaluation for possible rickets was negative. The patient was subsequently referred for genetics evaluation.
On examination at 14 months of age, his weight was 8.4 kg (5th–10th percentile) and head circumference was 47.3 cm (50th percentile); length measurement was limited because of joint contractures. He cried when he was moved. Frontal bossing, low-set ears, and a depressed nasal bridge with a bulbous nasal tip (Fig 2A) were observed. There was no hepatosplenomegaly. Hyperpigmented patches were noted over his metacarpophalangeal joints, elbows, malleoli, and spine (Fig 2 A and B), and his skin was shiny and thickened, with papules evident on his face and neck. There were contractures of the small and large joints of all 4 extremities (Fig 2A), and his back seemed stiff. At 14 months of age, he could not roll or sit because of contractures; however, he could point at objects. He was quite social, and speech development was normal. Lysosomal enzyme testing and a peripheral blood karyotype were unremarkable. An ophthalmology examination demonstrated myopia. A skin biopsy showed deposition of hyaline material in the dermis, and, on the basis of the clinical picture, systemic hyalinosis was suspected. ANTRX2 mutation analysis was performed.
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The patient developed progressive enlargement of soft tissue masses of the face (Fig 2 C and D) and pearly papules on the face (Fig 2D) and neck. Pain was a significant and persistent problem and was treated with gabapentin with some relief. At 17 months of age, a fleshy perianal mass was observed (Fig 2E). He had failure to thrive with a weight at 17 months of age of 8.86 kg (<5th percentile or 50th percentile for 8 months of age). At 24 months of age he developed chronic diarrhea, and at 3 years of age he was admitted to the UCI with status epilepticus from hyponatremia accompanying fluid and electrolyte imbalance. He required ventilatory support and died after support was discontinued at his family's request.
Patient 3
A Mexican American girl was born to nonconsanguineous parents at 41 weeks' gestation. The family history was negative for birth defects, mental retardation, or genetic disorders. Results of a prenatal ultrasound at 36 weeks were normal; however, at 41 weeks, oligohydramnios developed. Her birth weight was 3381 g (50th–75th percentile). At 4 months of age, her mother reported that she cried with any passive movement and with feeding. At 5 months of age, she developed hyperpigmented patches over her malleoli and metacarpophalangeal joints, and progressive joint contractures were evident. A radiographic skeletal survey at 6 months demonstrated osteopenia, periosteal reaction, and bilateral dislocated hips. She underwent extensive evaluations by multiple specialists, but the results were inconclusive. Skin fibroblasts were tested for lysosomal storage diseases, including Farber lipogranulomatosis; however, the results were negative. Peripheral blood karyotype was normal. Because of concern for an underlying malignancy, a bone marrow biopsy was performed at 7 months of age. The results were normal. An excisional biopsy of a periarticular nodule of the left ankle demonstrated fibrous proliferation, although a specific diagnosis could not be made. Gastroenterologic complaints were prominent. At 7 months of age an upper gastrointestinal study demonstrated gastroesophageal reflux, and at 9 months of age an endoscopy demonstrated duodenitis. She had a history of emesis, and a gastrostomy tube was placed at 18 months of age. A perianal mass developed at 20 months, followed by the development of cutaneous masses and progressive contractures resistant to prednisolone and penicillamine.
After being lost to follow-up for a number of years, she was reevaluated at 10 years of age. On examination, her weight was 25.6 kg (5th percentile) and head circumference was 51 cm (25th percentile). She used a wheelchair because of significant contractures that limited her mobility. She appeared older than her stated age, with a slightly coarse facial appearance (Fig 3). A prominent chin, papules over the nose (Fig 3A), a depressed nasal bridge, and thick alveolar ridges were evident. Masses were located on the inner lower lip and posterior neck. Her ears were prominent, with masses over the pinnae (Fig 3B). The liver edge was palpable 7 cm below the costal margin. She had hyperpigmented patches over her elbows, knees, and ankles (Fig 3 C and D), and the skin was firm to palpation. Her extremities demonstrated significant contractures of the large and small joints (Fig 3 C–E). The flexion creases of the fingers were intact, but she had extremely limited ability to flex her fingers. Her neck displayed limited range of motion, and she could not fully open her mouth. The contractures severely limited her daily activities. She could not feed herself or comb her own hair. She used her second and third fingers to hold a pencil and write in a regular school setting. Her cognitive development was normal. She did not complain of pain at rest. She had a history of recurrent perianal masses and auricular masses despite surgical resection. A clinical diagnosis of systemic hyalinosis was made, and analysis of ANTRX2 revealed mutations consistent with the clinical phenotype.
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RESULTS OF GENETIC TESTING |
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TOPABSTRACTCLINICAL CASESRESULTS OF GENETIC TESTINGDISCUSSIONCONCLUSIONSREFERENCES |
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Mutation analysis of ANTRX2 in the patients described in this report confirmed the initial clinical diagnosis of systemic hyalinosis (Table 1). Patient 1 was homozygous for a mutation (insertion of 1 C nucleotide, c.1605-1612insC) in exon 13 (Fig 4B), which predicted a premature stop codon in exon 13 of the protein. The mother was heterozygous for this mutation (Fig 4A). The father was not available for testing. Patient 2 likely carries a homozygous distal deletion of ANTRX2 spanning exons 14–17. This result was based on the absence of amplifiable DNA from this contiguous region despite amplification of all other exons in the affected child (data not shown). The entire gene, including exons 14 to 17, was amplified in both parents' DNA samples. Furthermore, control genes could be amplified in the sample of patient 2, indicating the integrity of the sample. Patient 3 was found to be a compound heterozygote, with 1 ANTRX2 allele containing a mutation in exon 13 (insertion of 1 C nucleotide, the same mutation as in patient 1) and the other allele harboring a nonsense mutation (c.1833C
T, p.R432X) in exon 15 predicting a more distal ANTRX2 truncation (Fig 4C). The parents each carried 1 of these mutations (data not shown).
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DISCUSSION |
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TOPABSTRACTCLINICAL CASESRESULTS OF GENETIC TESTINGDISCUSSIONCONCLUSIONSREFERENCES |
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The 3 patients in this report demonstrate the distinctive phenotype of systemic hyalinosis and associated causative mutations in the ANTRX2 gene. As illustrated by these cases, systemic hyalinosis is characterized by the presence of significant pain with passive movement and characteristic skin lesions (ie, hyperpigmented patches over the bony prominences, perianal masses, and pearly papules of the face and neck). The preauricular fleshy nodules in patient 1 may be an uncommon manifestation in this disorder given their irregular shape and association with unusual-appearing auricles, although they could represent a coincidental finding. Key clinical features of this condition are set forth in Table 2.
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The differential diagnosis of chronic pain and progressive contractures in infancy is limited but includes lysosomal storage disorders. All 3 of our patients had normal enzymatic studies for various lysosomal storage diseases, including a workup in patient 3 for Farber lipogranulomatosis. Farber disease presents with pain, skin nodules (often overlying joints), and hoarseness in infancy, and it can adversely affect cognitive development. By contrast, children with systemic hyalinosis are cognitively normal. Such sparing of the central nervous system is not surprising given the paucity of ANTRX2 expression in the normal human brain.7 Systemic hyalinosis is also differentiated from lysosomal storage disorders by the accompanying extracellular accumulation of abnormal hyaline material in the dermis in systemic hyalinosis,8–10 as opposed to intracellular accumulation in lysosomes in the lysosomal storage diseases.
The unusual physical findings in systemic hyalinosis may suggest a multiple malformation syndrome and prompt cytogenetic analysis. However, normal karyotypes have been documented in all affected individuals in whom chromosomal analysis has been undertaken.11–13 The perianal masses observed in systemic hyalinosis have been mistaken for condylomata, which can prompt an unnecessary workup for an infectious etiology such as human papilloma virus infection. Abnormal skeletal radiographs may prompt an evaluation for nonaccidental trauma, as in 1 of the children presented here. Appropriate recognition of the clinical presentation of systemic hyalinosis and genetic analysis of ANTRX2 can facilitate appropriate diagnosis and management.
Previous studies, possibly providing insight into the pathophysiology of this disorder, have suggested that mutations in ANTRX2 abrogate normal cell interactions with the extracellular matrix5; however, the exact pathophysiology by which mutations in ANTRX2 result in the phenotype of systemic hyalinosis is unknown. ANTRX2 point mutations were identified in 2 of the 3 patients in this report. Patient 1 was homozygous for a mutation predicting a loss of the cytoplasmic tail of the molecule. Mutations in this region have been described in other individuals with severe systemic hyalinosis, suggesting that this may be a hot spot for mutation.6 The homozygous mutation in patient 1 and maternal heterozygosity raise the possibility of unrecognized parental consanguinity; however, uniparental disomy was not excluded. Interestingly, patient 3, who had milder manifestations of disease, exhibited a novel mutation predicting a more distal truncation mutation on one allele and the same mutation as patient 1 on the other allele, which may suggest that some preserved function of ANTRX2 may lead to a milder course of disease. Patient 2 likely has a deletion in ANTRX2, and this would represent the first example of a deletion mutation in systemic hyalinosis. It would be predicted that the nature and location of ANTRX2 mutations would correlate at least partially with the clinical phenotype. Future study of ANTRX2 genotype and protein function may clarify the basis of severe and mild forms of systemic hyalinosis.
Although the 3 patients described in this report were Mexican in ancestry, children of diverse ancestry have been diagnosed with systemic hyalinosis. Given the complex nature this disorder, we suggest a multidisciplinary approach to care. A geneticist can help with diagnostic evaluation and ANTRX2 analysis. Although a skin biopsy can aid in the diagnosis, it may be nondiagnostic, as illustrated in 2 of our cases. Because pain is a primary and debilitating manifestation of this disorder, aggressive and scheduled use of analgesics is required. Gastroenterology expertise is essential because of the associated failure to thrive, protein-losing enteropathy, and feeding problems. A baseline echocardiogram may be useful, although few reports have documented significant hyalinosis of the heart,9 and the 3 patients in this report had normal echocardiogram results. When dermal masses are large or prevent proper oral function, surgery may be needed. In fact, anesthesia consultation is important because of the possibility that oral/facial lesions may obstruct the airway or present difficulty with elective intubation. Also, in this chronic and progressive disease, a palliative care team and mental health professionals can serve invaluable functions because of the associated high morbidity and mortality.
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CONCLUSIONS |
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TOPABSTRACTCLINICAL CASESRESULTS OF GENETIC TESTINGDISCUSSIONCONCLUSIONSREFERENCES |
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Systemic hyalinosis is an autosomal recessive disorder characterized by severe and chronic debilitating pain, progressive joint contractures, and distinctive skin lesions with abnormal accumulation of hyaline material in the dermis. Although ANTRX2 mutations allow for genetic confirmation of the diagnosis, the pathophysiology and treatment of systemic hyalinosis require additional study. Mortality in the 2 patients presented herein resulted from failure to thrive and complications related to gastrointestinal dysfunction. We suspect that loss of ANTRX2 function in the gastrointestinal tract explains these symptoms; therefore, future studies analyzing the normal function of the ANTRX2 protein are crucial to exploring treatment modalities. The development of compounds that compensate for the lack of ANTRX2 function seems a logical avenue of investigation.
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ACKNOWLEDGMENTS |
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We thank Drs Jennifer Foreman (Santa Clara Valley Medical Center), Eliott Sherr (University of California, San Francisco Pediatric Neurology), Julie Neidich and Risa Peoples (former Stanford medical geneticists), and the pediatric pain management clinic at Stanford for clinical expertise in the evaluation and care of these children.
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FOOTNOTES |
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Accepted May 24, 2006.
Address correspondence to H. Eugene Hoyme, MD, Department of Pediatrics, H-315, Stanford University School of Medicine, Stanford, CA 94305-5208. E-mail: gene.hoyme{at}stanford.edu
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2006 by the American Academy of Pediatrics
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