NORD is very grateful to Thomas Lücke, MD, PhD, Department of Neuropediatrics Children's Hospital, University of Bochum, Bochum, Germany, for assistance in the preparation of this report.
The multiple symptoms of SIOD and the relative frequency of them are listed in the table. The symptoms are subsequently discussed in 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 individuals 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 differed 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, we postulate that it accentuates the vascular disease of SIOD; however, renal transplantation does not prevent progression of the atherosclerosis.
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 and one patient had extensive fatty infiltration resembling that of arrhythmogenic right ventricular cardiomyopathy.
Central nervous system (CNS)
The central nervous system shows both mutiple 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 phenomenon.
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.
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%). However, in addition to a deficit of T lymphocytes, the hematopoietic disturbance can include any or all other blood cell lineages.
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.
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 as an autosomal recessive disorder. This indicates that the parents of an affected individual must carry at least one copy of the mutant gene. For the siblings of a patient, the risk of being affected is 25% and for being a carrier is 50%. Heterozygous carriers do not show any disease traits.
Biallelic 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 biallelic mutations in SMARCAL1 have had SIOD and none of the tested unaffected siblings have had biallelic mutations. The asymptomatic boy with biallelic 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 is located in chromosomal region 2q34-q36. The SMARCAL1 gene encompasses approximately 70 kilobases and contains 18 exons. It encodes an enzyme with two HARP domains and a sucrose nonfermenting type 2 (SNF2) domain. Other SNF2 family members encode enzymes that hydrolyze ATP to cause changes in chromatin structure. Such changes in chromatin structure allow other modifications of DNA and chromatin including the modulation of gene expression.
The precise function of the SMARCAL1 enzyme remains undefined. The enzyme recognizes DNA structure, not a specific DNA sequence(s). It binds chromatin and hydrolyzes ATP in the presence of the specific DNA structures, but it does not promote detectable nucleosome mobility or exhibit helicase activity. Additionally, from clinical studies it does not appear to be involved in DNA repair because SIOD patients do not have hypersensitivity to ultraviolet or ionizing radiation, genomic instability, or increased incidences of cancer. Nor does it appear to be involved in the regulation of the vasodilatory factor nitric oxide or in mitochondrial function because both of these functions are intact in SIOD patients. Vascular and pulmonary complications of SIOD cause morbidity and mortality; SMARCAL1 deficiency seems to be associated with altered expression of elastin transcriptional regulators, severely decreased expression of elastin mRNA and protein and impaired elastogenesis.
Ongoing studies have shown that deficiency of SMARCAL1 causes non-random, global changes in gene expression. Based on this it has been hypothesized that SMARCAL1 modulates gene expression either via regulation of genomic neighborhoods or by acting as a general transcription factor. A hint of how modulation of gene expression might cause disease has come from the observation that adolescent and adult patients have very few neural progenitors or stem cells and from the finding that removal of Smarcal1 from mouse neural progenitors impairs their growth and proliferation. These findings suggest that loss of SMARCAL1 causes disease by impeding tissue renewal from stem cells or early progenitors.
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, 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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