NORD gratefully acknowledges Cornelius Boerkoel, MD, PhD, Provincial Medical Genetics Program, University of British Columbia, Department of Medical Genetics, Children's and Women's Health Centre of BC; David B. Lewis, MD, Division of Allergy, Immunology, and Rheumatology, Department of Pediatrics, School of Medicine, Stanford University; and Thomas Lücke, MD, PhD, Department of Neuropediatrics Children's Hospital, University of Bochum, Bochum, Germany, for assistance in the preparation of this report.
Schimke immuno-osseous dysplasia (SIOD) is a multisystem disorder that is inherited in an autosomal recessive pattern. It usually manifests first with growth failure. Other features of the disease are generally noted in the ensuing evaluation of the growth failure or develop in the following years. According to the severity of the clinical features and the age of onset, SIOD has been divided into an infantile or severe early-onset form and a juvenile or milder late-onset form. Affected individuals with early-onset manifest severe symptoms and have a mean age of death at 9.2 years. These individuals have died from strokes, severe opportunistic infections, bone marrow failure, complications of kidney failure, congestive heart failure, and unspecified lung disease. On the other hand, those with milder disease have survived into the fifth decade if symptomatically treated. However, severity and age of onset of symptoms do not invariably predict survival as a few of those with early-onset disease have survived into the third and fourth decade.
The multiple symptoms of SIOD and the relative frequency of them are listed in the table. The symptoms are subsequently discussed according to the organ system affected.
Most affected individuals have distinctive physical features. These include fine hair (60%), a thin upper lip, a broad, low nasal bridge (68%), a bulbous nasal tip (83%), and disproportionately short stature (98%). Additional features include excessive inward curvature of the lumbar spine (lumbar lordosis, 84%), a protruding abdomen, and hyperpigmented macules (85%) on the trunk and occasionally on the neck, face, arms and legs. Less common physical features include absent or small teeth and corneal opacities (19%).
Growth and Skeletal System
Growth failure, which is often the first obvious sign of SIOD, occurs despite normal growth hormone production and is not corrected with growth hormone supplementation. In most affected individuals, the growth failure begins prior to and continues after birth; however, some affected children do have normal birth lengths and weights and their growth failure is not noted until after birth (range: 0 to 13 years, mean: 2 years). The heights of those who survived to adulthood were 136-157 cm for men and 98.5-143 cm for women.
The short stature arises generally because of spondyloepiphyseal dysplasia (86%), a disorder of skeletal growth; it does not arise as a complication of their renal failure. The anthropometric characteristics of patients with SIOD differ markedly from those of patients with other forms of chronic kidney disease, especially with respect to median leg length and sitting height. The spinal column and hip joint are most severely affected. The radiological abnormalities include ovoid or mildly flattened vertebral bodies, small and laterally displaced femurs (thigh bone), and shallow abnormal acetabular fossae (hip sockets). Less frequent skeletal problems include lordosis, kyphosis and scoliosis (abnormal curvatures of the spine) as well as osteopenia (decreased bone mineral density) and degenerative hip disease. Many patients have required hip replacements.
Approximately 42% of individuals with SIOD have reduced thyroid function. However, to date, the poor thyroid function has not caused clinical symptoms (subclinical hypothyroidism). Among those who have received thyroid hormone supplementation, the correction of thyroid hormone levels does not mitigate other symptoms of SIOD.
All reported affected individuals have eventually developed renal dysfunction. The kidney disease is characterized by progressively worsening loss of protein in the urine and ultimately concludes with renal failure. The progressive renal disease is not responsive to immunosuppressant therapy. The diagnosis of renal dysfunction is usually made concurrent with or within the five years following the diagnosis of the growth failure. Renal failure requiring dialysis or kidney transplantation usually develops within the subsequent 11 years, although the rate of progression varies greatly. Because renal disease causes high blood pressure and high levels of blood cholesterol and lipids, the theory is that it accentuates the vascular disease of SIOD; however, renal transplantation does not prevent progression of the atherosclerosis. The incidence of a single kidney may be higher than in the unaffected population and this is associated with a more rapid onset of renal failure.
Half of SIOD individuals develop clinical signs of atherosclerosis. The onset is often in early childhood and relentlessly progressive. The disease is not abrogated by renal or bone marrow transplantation nor by cholesterol lowering agents, although the cholesterol lowering agents and renal transplantation can slow the progression by mitigating factors such as high blood pressure and high blood lipid and cholesterol levels. Consistent with the atherosclerosis resulting from an intrinsic defect of SIOD tissue, the vascular disease does not recur in the transplanted kidneys. Besides atherosclerosis, splitting and fraying of the arterial internal elastic layer and thickening of the muscular layer of the arterial walls have been found on autopsy. The latter finding may be a complication of high blood pressure or an intrinsic defect in the blood vessels. A few patients have also developed subaortic stenosis, one patient showed severe bicuspid aortic stenosis and one patient had extensive fatty infiltration resembling that of arrhythmogenic right ventricular cardiomyopathy.
Central nervous system (CNS)
The central nervous system shows both multiple developmental and ischemic changes. The developmental defects include brain malformations suggestive of aberrant neuronal migration including heterotopia, irregular cortical thickness, incomplete gyral formation, poor definition of cortical layers, and hamartia. Additionally, adolescent and adult patients have very few neural progenitors (stem cells). Despite these malformations, most SIOD patients have normal social, language, motor, and cognitive development until the onset of symptoms from reduced brain blood supply (cerebral ischemia).
The cerebral ischemia can either temporarily or permanently disturb the blood supply of a given area of the brain and thereby cause temporary (47%, transient ischemic attacks) or permanent (44%, strokes) dysfunction. The cerebral ischemic attacks and strokes are often precipitated by acute changes in blood pressure, such as following the administration of high doses of steroids. Ischemic changes include loss of neurons and myelin, gliosis (scarring), brain atrophy, and degeneration of infarcted regions including atrophy of the cerebellum. Likely as a complication of the cerebral ischemia and atherosclerosis, a few of the patients have also manifest Moyamoya disease.
Another common neurological feature in SIOD patients is severe migraine-like headaches (60%). The cause of the headaches is still unknown but they tend to be more severe and refractory to anti-migraine medications that migraine-like headaches in the general population. In one patient a reversible cerebral vasoconstriction syndrome was suspected.
Several patients have died from pulmonary complications including pulmonary emboli, pulmonary hypertension, and lung disease. Lung abnormalities identified by autopsy include diffuse thickening (hyperplasia) of the airway (bronchial) smooth muscles, enlargement (emphysematous changes) of the gas exchange regions (alveoli), and diffuse hyperplasia of the pulmonary artery smooth muscles. The last finding could account for the pulmonary hypertension observed in some patients.
Hematopoietic and Immune Systems
Nearly all affected individuals have some blood cell deficiency. Deficiency of T lymphocytes, a subgroup of white blood cells that plays an important role in immunity, is most common (97%) and is usually present at birth. Reductions in both CD4 T cells, which regulate multiple aspects of the immune system and CD8 T lymphocytes, which are important in the control of viruses are typical. However, in addition to a deficit of T lymphocytes, the hematopoietic disturbance can include any or all other blood cell lineages. These hematopoietic cell deficiencies reflect reduced production of these cells by the bone marrow, and affected individuals are more prone than unaffected ones to developing decreased hematopoietic cell levels in the blood as a side effect of drug therapy. Affected individuals are also less responsive to the effects of G-CSF therapy to increase bone marrow production of neutrophils and erythropoietin therapy to increase the bone marrow production or red blood cell precursors.
Because of their immunodeficiency, affected individuals have an increased risk for opportunistic fungal, viral and bacterial infections. They also have an increased risk of more severe infections. The immunodeficiency is also associated with immune dysregulation disorders, such as autoimmune blood diseases.
Few SIOD patients have reached sexual maturity and of the ones who have, no children were subsequently born. However, the patients who have survived to adulthood did develop with secondary sexual characteristics and the women have menstrual cycles. The autopsy of two affected males revealed that sperm production was affected in a varying degree. In one patient, the testes showed interstitial fibrosis and absence of sperm (azoospermia), whereas the other had less interstitial fibrosis individual and produced some sperm.
SIOD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent. If an individual receives one normal gene and one abnormal gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Two mutations in the swi/snf-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a-like 1 (SMARCAl1) gene are found in 50 to 60% of individuals clinically diagnosed with SIOD. The individuals without detectable mutations in SMARCAL1 have a lower frequency of hyperpigmented macules and lymphopenia and higher frequency of cognitive impairment. This suggests that they have might have a subtly different disorder or SIOD secondary to another genetic cause.
The mutations identified in SMARCAL1 suggest that SIOD arises from loss of function in the encoded protein. These mutations include gene deletions as well as nonsense, frame shift, splicing and missense mutations. Mutations in SMARCAL1 have not been found to cause any other disease.
With the exception of the sibling of an affected patient, all identified patients with two mutations in SMARCAL1 have had SIOD and none of the tested unaffected siblings have had two mutations. The asymptomatic boy with two mutations was 2 years when first described and may develop symptoms later.
Despite extensive analysis, there are no predictable relationships between particular SMARCAL1 mutations and the severity of the symptoms or the outcome. This has led to the idea that SIOD is the result of the interaction between the SMARCAL1 mutations and environmental, genetic, and epigenetic factors.
The SMARCAL1 gene encodes the SMARCAL1 enzyme which has a role in DNA repair and the DNA stress response, participates in activating stalled DNA replication forks and reannealing single stranded DNA to double stranded DNA. SMARCAL1 deficiency in tissue culture cells also impairs normal replication of telomere DNA at the ends of the chromosomes. Recent studies of some SIOD patients with SMARCAL1 deficiency caused by two SMARCAL1 mutations has found significantly shortened telomeres in white blood cells, including T cells. The deficiency of SMARCAL1 causes non-random, global changes in gene expression and changes in gene expression cause the arteriosclerosis, renal disease and immunodeficiency. The arteriosclerosis appears to be a consequence of reduced expression of elastin. The renal disease appears to arise from overexpression and activity of the WNT and NOTCH pathways. The T-cell deficiency arises from lack of expression of IL7 receptor alpha chain expression and is associated with hypermethylation of the IL7R promotor as well as the shortened telomere length. These changes in gene expression might well develop from the changes in epigenetic marks associated with replication fork stalling and collapse.
SIOD is panethnic with an unknown prevalence. As deduced from referrals and published birth rates, the incidence is approximately 1 per million live births in North America.
The diagnosis of SIOD is made on clinical findings. The most definitive diagnostic findings are skeletal dysplasia (spondyloepiphyseal dysplasia), renal dysfunction (urinary protein loss), T lymphocyte deficiency (particularly for naïve CD4 and CD8 T cells), dysmorphic facial features, and hyperpigmented macules. Anthropometry can help to distinguish SIOD from other forms of chronic kidney disease: a sitting height: leg length ratio of < 0.83 is consistent with a diagnosis of SIOD whereas a ratio of > 1.01 is indicative of non-SIOD chronic kidney disease. DNA testing for mutations in the SMARCAL1 gene is available to confirm the diagnosis.
Treatments are selected to address individual symptoms as they develop. Renal transplantation effectively treats the renal disease, and bone marrow transplantation effectively treats the immunodeficiency and other hematological abnormalities. Blood thinning medications such as pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin and heparin can transiently improve blood flow through the atherosclerotic arteries but do not provide enduring relief from cerebral ischemia. Treatment with acyclovir and some antibacterial agents has been beneficial for preventing or reducing the frequency of opportunistic infections. Hip replacement effectively treats the degenerative hip disease.
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