Alpha-Thalassemia/Mental Retardation syndrome, Chromosome 16-Related

What is Alpha-Thalassemia/Mental Retardation syndrome, Chromosome 16-Related?

Alpha-Thalassemia/Mental Retardation syndrome, Chromosome 16-Related is a rare disease. It is also known as Alpha-thalassemia/mental Retardation Syndrome, Deletion-type Atr-16 Syndrome Atr, Deletion-type ATR1 Chromosome 16p Deletion Syndrome Haemoglobin H disease Hemoglobin H-related Mental Retardation; Hbhr Mental Retardation With Hemoglobin H.

Syndrome Overview:
Alpha-Thalassemia/Mental Retardation syndrome, Chromosome 16-Related is a contiguous gene syndrome characterized by alpha-thalassemia and a variable degree of facial dysmorphism and intellectual disability. ATR-16 syndrome is caused by deletions in the chromosome 16p13.3 region.

Clinical Description:
In addition to alpha thalassemia, there is mild-to-moderate intellectual disability and a rather non-specific spectrum of dysmorphic features. There is a tendency toward a tall or broad forehead, hypertelorism, horizontal or downslanting palpebral fissures, long or relatively simple philtrum, crowded or irregularly spaced teeth, and depressed nasal bridge in infancy that could become more prominent later in life. Macrocephaly or microcephaly can be present. Talipes equinovarus and cryptorchidism are common, and there may be a tendency toward obesity.

Patients with this condition have deletions around 16p13.3. Disease-causing deletions can include alpha-globin genes and/or distal regulatory elements (Ferrao et al., 2017).

Gibbons (2012) reviewed the clinical and molecular characteristics, as well as diagnostic criteria, for alpha-thalassemia/intellectual disability syndrome, chromosome 16 related, X-linked alpha thalassemia intellectual disability and alpha-thalassemia myelodysplastic syndrome.

Prenatal Presentation:
Quadrifoglio et al., (2016) described a 17-week-old fetus with prenatal diagnosis of intracranial mass. Molecular testing revealed a 948-kb de novo microdeletion in the 16p13.3 region, including the ATR-16 syndrome region. On the postmortem examination, short neck, microphthalmia, triangular face and extraventricular neurocytoma were found.

Genotype-Phenotype Correlations:

The non-deletion, X-linked form of this condition - Alpha-Thalassemia X-Linked Intellectual Disability Syndrome (ATRX) - has a more predictable phenotype, which includes severe intellectual disability and characteristic facial features.

Molecular Genetics:
Holinski-Feder et al., (2000) studied a large dominant pedigree segregating for mild-to-moderate intellectual disability and mild, non-specific dysmorphic features and demonstrated a cryptic 16p13.3 translocation associated with translocation of terminal 3q.

Pfeifer et al., (2000) showed the SOX8 gene was deleted from 16pter in a patient with ATR-16 syndrome.

A male patient with 45X karyotype and a submicroscopic unbalanced Y;16p11-13 translocation reported by Kellermayer et al., (2005) had this condition.

Brown et al., (2000) reported a 4-month-old male with a 16p13.3-pter deletion who had scaphocephaly with sagittal craniosynostosis, seizures, subcortical and subependymal tubers and multiple cysts of the kidneys. A 12-color multiplex FISH telomere assay demonstrated a (16;19)(p13.3;p13.3) translocation in the mother, with an unbalanced 16p13.3 deletion in the child.

A female reported by Akahoshi et al., (2005) with a 16p13 duplication clinically looked like ATR-X.

Harteveld et al., (2007) have developed a rapid method of detecting rearrangements involving the tip of chromosome 16, and three patients were detected. A search for telomeric loss should be carried out in all those with intellectual disability and persistent microcytic, hypochromic anemia.

The case reported by Gibson et al., (2008) had a submicroscopic deletion. Dysmorphic facial features were mild (high forehead, prominent nasal root and bridge, upslanting palpebral fissures, high palate, and anterior frenulum).

Bezerra et al., (2008) described a family with a 0.97- to 1.05-Mb deletion in chromosome 16p13.3, including exon 1 and 3 of the SOX gene plus other genes. Clinical characteristics included microcytic hypochromic anemia and thalassemia, without any other ATR-16 characteristics (intellectual disability, dysmorphic features).

Regueiro-García et al., (2015) reported a patient with classical features of ATR-16 syndrome with a 2.2-Mb deletion in chromosome 16p13.3. He developed osteosarcoma at age 14, for which he underwent chemotherapy and later amputation.

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* This information is courtesy of the L M D.

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What gene changes cause Alpha-Thalassemia/Mental Retardation syndrome, Chromosome 16-Related?

The syndrome is inherited in the following inheritance pattern/s:

Autosomal Dominant - In the case of autosomal dominant inheritance, just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.


Microdeletion - Microdeletion inheritance occurs when there is a deletion of several genes on a chromosome. The specific chromosome on which the deletions occur will determine the syndrome they cause.


In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.

OMIM Number - 141750 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
HBA1 - 16p13.3
HBA2 - 16p13.3

What are the main symptoms of Alpha-Thalassemia/Mental Retardation syndrome, Chromosome 16-Related?

The typical symptoms of the syndrome are:
Micrognathia, Microtia, Micropenis, Macroglossia, Long philtrum, Low-set, posteriorly rotated ears, Neurological speech impairment, Anteverted nares, Intellectual disability, Muscular hypotonia, Autosomal dominant inheritance, Retrognathia, Triangular nasal tip, Webbed neck, Short neck, Pectus carinatum, Patent ductus arteriosus, Seizure, Epicanthus, Flat forehead, Dental crowding, Malar flattening, Flexion contracture, Cryptorchidism, Downslanted palpebral fissures, Short stature, Hypospadias, Short toe, Underdeveloped supraorbital ridges, Hypertelorism, Cognitive impairment, Depressed nasal bridge, High forehead, Broad forehead, High palate, HbH hemoglobin, Reduced alpha/beta synthesis ratio, Protruding tongue, Radial deviation of finger, Supernumerary nipple, Microcephaly, Talipes equinovarus, Phenotypic variability, Contiguous gene syndrome, Ptosis, Abnormal serum ferritin, Frontal bossing, Hypochromic microcytic anemia, Abnormal circulating porphyrin concentration, Aplasia/Hypoplasia of the eyebrow, Asym

How does someone get tested for Alpha-Thalassemia/Mental Retardation syndrome, Chromosome 16-Related?

The initial testing for Alpha-Thalassemia/Mental Retardation syndrome, Chromosome 16-Related can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

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