Introduction
ATR-X syndrome or alpha thalassemia X-linked intellectual disability is a rare inherited X-chromosome-associated disorder that affects the red blood cells (RBCs) and diminishes intellect to some extent. The condition was first reported in 1990. The condition mostly shows symptoms in males.
Who Is Susceptible to ATR-X Syndrome?
ATR-X syndrome is a rare X-linked disorder and has been reported in more than 200 individuals through molecular genetic testing. Most of these cases presented with severe symptoms, which are considered the extreme end of the spectrum, while children have been diagnosed with a milder form of the disease. The true prevalence and incidence are yet under study. Female carriers do not usually exhibit any clinical symptoms. The age of onset varies between four weeks to 24 months. The prevalence of the condition at birth in Japan stands at one in 60,000 to 80,000 births, as per the latest studies.
What Causes ATR-X Syndrome?
ATR-X syndrome is caused by mutations in the ATRX gene. Since the syndrome is an X-linked recessive genetic condition, the aberrant gene has to be inherited from one parent (maternal) in males to be clinically perceptible. Daughters are usually carriers who then can possibly mother an affected child (a 50 % probability). The ATRX gene is located on the long arm (q) of the X-chromosome (Xq13.3). Females who carry the mutated gene are intellectually typical with no clinical manifestations due to a process known as marked skewing of X chromosome inactivation in which one of the X-chromosomes gets inactivated during fetal development. In some cases, the X-chromosome carrying the mutated gene gets inactivated.
What Is the Pathophysiology of ATR-X Syndrome?
The ATRX gene encodes proteins that play an essential role in the normal development of the body. The exact function of the ATRX gene is still under study, but some successes indicate it helps regulate the expression of other genes like HBA1 and HBA2 which are necessary for normal hemoglobin synthesis. These mutations cause abnormal expression leading to alpha thalassemia. Other studies reveal that ATRX gene mutations reduce the expression of certain genes resulting in developmental delay, distinctive facial features, and other clinical manifestations of ATR-X syndrome.
What Are the Signs and Symptoms of ATR-X Syndrome?
The signs and symptoms of ATR-X syndrome are:
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Late learning to walk.
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Lack of speech.
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Partial bowel control.
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Partial bladder control.
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Aggressive behavior.
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Communication difficulties.
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Autistic traits.
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Short height.
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Small head size.
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Poor suckling in newborns.
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Gastroesophageal reflux disorder.
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Pneumonia from reflux.
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Dribbling of saliva.
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Constipation.
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Severe abdominal pain.
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Volvulus (looping or twisting of the intestine).
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Seizures (convulsions).
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The deficient foreskin on the penis.
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Undescended testes (cryptorchidism).
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Micropenis (small penis).
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Clubfoot (deformed foot).
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The curvature of the spine.
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Urinary tract infections.
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Sleep disturbances.
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Abnormal hemoglobin levels.
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Abnormality of fontanelles.
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Abnormality of movement.
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Tooth abnormalities.
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Facial anomalies.
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Abnormality of the kidney.
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Aganglionic megacolon (large intestine abnormality due to lack of nerve supply).
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Agenesis of corpus callosum (brain disorder).
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Intersex genitalia.
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Anemia (deficient blood cells).
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Anteverted nares (upturned nostrils).
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Cognitive abnormalities.
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Perceptual abnormalities.
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Blindness.
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Brachydactyly (short digits).
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Cerebral cortical atrophy (loss of brain cells).
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Clinodactyly of the fifth finger (curved pinky finger).
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Depressed nasal ridge (saddle nose).
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Depression.
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Dysphasia (language disorder).
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Epicanthus (eyelid deformity).
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Everted lower lip vermilion.
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Tented upper lip vermilion.
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Flat face.
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Flexion contracture.
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Hydronephrosis (severe distention of the kidney).
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Hypertelorism (wide-spaced eyes).
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Hypoplasia of the penis.
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Hypotonia (low muscle tone).
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Infectious encephalitis.
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Joint stiffness.
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Macroglossia (large tongue).
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Male pseudohermaphroditism.
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Midface retrusion.
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Nausea.
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Vomiting.
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Optic atrophy (death of optic nerve).
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Delayed mental milestones.
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Self-injurious behavior.
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Sensorineural hearing impairment.
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Short stature.
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Spastic paraplegia (a genetic disorder causing leg weakness and stiffness).
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Telecanthus (increased distance between eyes’ canthus).
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Pectus carinatum (bird-like chest).
How to Diagnose ATR-X Syndrome?
The diagnosis of ATR-X syndrome is suspected with clinical findings, hematologic studies, and familial history and is established with molecular genetic testing and epigenetic signature analysis.
The preliminary diagnosis is based on the clinical findings observed by the physician which are then confirmed by laboratory studies.
1. Hematologic Findings:
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HbH inclusions (β-globin tetramers).
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Red blood cell indices in Microcytic hypochromic anemia.
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HgH on newborn show hemoglobinopathies.
2. Familial History: Familial record is consistent with X-linked inheritance with a maternal carrier.
3. Molecular Gene Testing: The diagnosis is based on a male proband with suggestive findings and a hemizygous pathogenic variant in ATRX identified by molecular genetic testing. The testing includes a combination of gene-targeted testing (single and multi-gene panels) and comprehensive genomic testing. Single gene testing can be performed to detect small intragenic deletions or insertions and missense, nonsense, and splice site variants. The multigene panel can identify the genetic cause of the condition while limiting the identification of variants, and it does not explain the underlying phenotype.
Comprehensive genomic testing usually involves exome sequencing to detect the involved genes, and the exome array detects exon deletions or duplications. Other tests involve epigenetic signature analysis or methylation microarray of leukocytes.
How to Treat ATR-X Syndrome?
The treatment of ATR-X syndrome is symptomatic where each of the pertaining manifestations is managed sequentially with the concerned team of doctors. Pediatricians, surgeons, dentists, speech therapists, ophthalmologists, orthopedists, and other healthcare professionals may need to systematically and comprehensively tailor the patient’s treatment regime. Genetic counseling is advised to clarify the genetic status of family members. Prenatal and preimplantation genetic testing is advised during family planning once an ATRX pathogenic variant is detected in a family.
What Is the Prognosis of ATR-X Syndrome?
The condition was first reported in 1990 and as per the latest follow-ups, all reported cases were well in their 30s and 40s.
What Is the Differential Diagnosis of ATR-X Syndrome?
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Coffin-Lowry syndrome.
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Angelman syndrome.
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Smith-Lemli-Opitz syndrome.
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Pitt-Hopkins syndrome.
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MECP2 duplication syndrome.
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Hemoglobin H (HbH) disease.
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Fineman-Myers syndrome.
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Smith-Fineman-Myers syndrome.
What Are the Complications of ATR-X Syndrome?
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Severe myopia.
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Blindness.
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Deafness.
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Kidney failure.
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Congestive cardiac failure.
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Pneumonia.
Conclusions
ATR-X syndrome is an inherited disease that has a maternal origin. The condition shows early signs and symptoms that can be managed with interdepartmental cooperation. While all affected individuals have a normal 46, XY karyotype, the external genitalia may sometimes be ambiguous. The parents, with familial history of ATR-X syndrome, must consider genetic counseling prior to family planning. The pregnant mother should undergo prenatal genetic screening in which a sample from peripheral blood or from the amniotic fluid can be tested for genetic abnormalities. Genetic karyotyping may be conducted to detect any chromosomal or genetic abnormality. The condition requires better understanding and research from which accurate treatment protocols can be derived. Due to the fresh nature of the condition, the unknown far weighs over the known, and future studies would aid in a better understanding of the pathophysiology, nature, and remedies of the disease.
