Aase - triphalangeal thumb; congenital anaemia

What is Aase - triphalangeal thumb; congenital anaemia?

Aase - triphalangeal thumb; congenital anaemia is a rare disease. It is also known as Aase - triphalangeal thumb; congenital anaemia Blackfan-Diamond syndrome Diamond-Blackfan syndrome.

Diamond-Blackfan anemia is characterized by congenital red blood cell aplasia. Additional features are craniofacial, limb, heart, and urinary system malformations. TSome individuals show growth retardation.
In a review of 200 cases of congenital erythroid hypoplastic anaemia, all thought to be the Blackfan-Diamond syndrome, seventeen individuals had abnormal thumbs. Nine had triphalangeal thumbs, three were duplicated and three were bifid. A flattened thenar eminence was found even when the thumbs appeared normal. Forty-five patients out of 133 in a separate series had another physical abnormality, including short stature, a webbed neck or a cleft palate. Hing and Dowton (1993) reported a female case with underdevelopment of the ilia, distal sacrum and coccygeal vertebrae.
Aase and Smith (1969) described two affected brothers. Murphy and Lubin (1972) reported a 2 1/2-year-old male with developmental delay, triphalangeal thumbs, hypoplastic anaemia, hypertelorism, a retinopathy, a cleft palate, a short, webbed neck, parietal foramina and scoliosis. His mother had a unilateral triphalangeal thumb, as did her brother and sister. Hurst et al. (1991) reported a mother with congenital hypoplastic anaemia who had a son with radial hypoplasia and anaemia.
Gojic et al. (1994) and Viskochil (1990) reported apparently dominant families where individuals in three generations were affected. McLennan et al. (1996) reported a mother with Blackfan-Diamond syndrome, but with no limb defects, where an affected fetus was picked up by ultrasound during pregnancy. At 22 weeks cardiomegaly and a small pericardial effusion were noted. A similar family was reported in 1988, but cardiac scans were normal until later in the pregnancy. However, no individuals in these families had radial or thumb defects. The anaemia responds to steroid therapy in two-thirds of patients and spontaneous remission can occur (Diamond et al. 1961; Dessypris, 1991). Nevertheless, many children become transfusion dependent on the associated complications of iron overload. Interleukin-3 (IL-3) therapy may produce an erythroid response in a subgroup of patients (Gillio et al. 1993). Janov et al. (1996) reviewed 76 cases from Boston Children's Hospital. They noted a 200 fold relative risk of leukaemia. Gustavsson et al. (1997) presented evidence for linkage of Diamond-Blackfan anaemia to 19q13. Four families showed dominant inheritance and one family recessive inheritance. A 1.8Mb critical region was identified through a deletion in one patient, together with a balanced X;19 translocation in another. The clinical features of the X;19 translocation case are reported by Gustavsson et al. (1997). Further evidence for mapping to 19q13 was presented by Gustavsson et al. (1998), including two cases with a microdeletion. However, there was evidence of locus heterogeneity in three families. Draptchinskaia et al. (1999) isolated the gene from the X;19 translocation and showed it to code for a ribosomal protein S19. Mutations in 10 out of 40 unrelated patients with Diamond-Blackfan anaemia were demonstrated, many of these were null mutations. Another ribosomal gene (S24) at 10q22-23 is also implicated (Gazda et al. 2006).
Cario et al. (1999) reported a boy with Diamond-Blackfan anaemia, severe hypotonia, macrocephaly, hypertelorism, a broad and tall forehead and developmental delay. Conventional karyotype was normal but a 3-Mb deletion at 19q13.2 was demonstrated by FISH analysis. This patient was originally reported by Gustavsson et al. (1998) as was the case reported by Tentler et al. (2000). Mutations in RPS19, RPS24, RPS17 and RPL35A account for about 30% of cases and Gazda et al. (2008) have reported mutations (especially involved with the phenotype involving a cleft palate and abnormal thumbs) in RPS5, RPS11 and RPS7.
Wang et al. (2015) described two unrelated patients with Diamond-Blackfan anaemia and germline mutations in RPL27 and RPS27. Heterozygous de novo splicing mutation in the RPL27 gene was found in a 2-year-old female patient diagnosed at birth with anaemia, atrial septal defect and pulmonary stenosis. Heterozygous de novo truncating mutation in the RPS27 gene was found in a 4-year-old female with anaemia and skin pigmentation. Both patients responded to steroid treatment. The authors summarized the data from 98 Japanese Diamond-Blackfan anaemia patients. The frequency of the patients harbouring mutations/large deletions in ribosomal protein genes was 55%.
Mirabello et al. (2017) described two families with Diamond-Blackfan anaemia due to heterozygous missense mutations in two previously unreported genes: RPL35 and RPL18. Characteristic symptoms were early-onset anaemia (either transfusion dependent or responsive to steroids), and ulcerative colitis (one patient). One family had neutropenia.
Arbiv et al. (2017) reviewed 45 patients with Diamond-Blackfan anaemia. Mutations were found in RPS19 (36%), RPL5 (16%), RPL11 (16%) and RPS26 (11%); other genes (RPS24, RPL35a, RPS17, RPS7, RPS10, RPS29) were less common. There were no differences in the age of presentation and the frequency of neutropenia and thrombocytopenia related to specific genes. Mutations in RPS19 were associated with more severe disease and mutations in RPL11 mutations with milder disease. Skeletal involvement was present in 39% of patients, cardiac malformations in 31%, craniofacial malformations in 23%, and genitourinary malformations in 22%.
van Dooijeweert et al. (2017) described clinical and molecular characteristics of the disorder in 43 Dutch patients. Mutations were found in 60.5% of patients, most frequently in the RPS19 gene (27.9%). The authors identified mutations in the novel gene, RPL9. In this cohort, 88.6% of the patients showed an initial response to steroid treatment.
Wlodarski et al. (2018) described six patients with heterozygous mutations in the RPL15 gene. Three of the four patients with protein-truncating mutations had prenatal onset of the disease, requiring in utero transfusions.

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* This information is courtesy of the L M D.

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What gene changes cause Aase - triphalangeal thumb; congenital anaemia?

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

Autosomal Recessive - Autosomal recessive inheritance means an affected individual receives one copy of a mutated gene from each of their parents, giving them two copies of a mutated gene. Parents, who carry only one copy of the gene mutation will not generally show any symptoms but have a 25% chance of passing the copies of the gene mutations onto each of their children.

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.

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 - 105650 (please check the OMIM page for updated information)

The syndrome can be caused by mutations in the following gene/s location/s:
RPS19 - 19q13.2

What are the main symptoms of Aase - triphalangeal thumb; congenital anaemia?

The typical symptoms of the syndrome are:

How does someone get tested for Aase - triphalangeal thumb; congenital anaemia?

The initial testing for Aase - triphalangeal thumb; congenital anaemia 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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