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Hereditary isolated congenital malformations such as congenital cataracts or anterior segment anomalies are usually considered to be the result of a single gene mutation. The identification of associated abnormalities—dysmorphic features, a malformation in another organ system, or mental handicap, help to identify those who carry more severe genetic defects such as chromosome rearrangements. We describe a family where two otherwise healthy men, a father and son, had juvenile cataracts. They both had offspring with more severe ocular anomalies including anterior segment dysgenesis, as well as mental retardation and dysmorphic features. Recent karyotype analysis revealed a balanced translocation in both father and son and a derived unbalanced translocation in their more severely affected children. Analysis of the translocation breakpoints led to the identification of a new human disease gene, MAF, in lens and anterior segment development.1 Critically, for the family, the finding of the translocation provides an explanation for the severe ocular and other anomalies in the individuals with the unbalanced derivative karyotype. In addition, it allows the option of prenatal diagnosis for future offspring for individuals carrying the balanced translocation.
A man with juvenile onset cataracts, and a family history of this, sought genetic advice with his partner. This man (II.3, Fig 1) was the father of three children with ocular anomalies and developmental delay. He had juvenile onset, progressive cataracts which were removed at the age of 24 years. The cataracts were described as widespread dot opacities, with anterior and posterior sutural densities. General and other ocular examination was normal.
This couple’s only living child, a daughter age 5 years (III.3, Fig 1), had been noted at birth to have opaque corneas, small lens remnants in each eye, and very flat anterior chambers with rims of abnormal iris tissue. Bilateral microphthalmia was present with axial lengths of 12 mm. Fundal examination and an ERG were normal. Bilateral corneal grafts were attempted, but rejection occurred. This child had significant developmental delay with learning and motor difficulties, saying approximately five single words and only just walking at the age of 5 years. She had microcephaly and dysmorphic features (Fig 2A and B).
Two previous siblings, now dead, had also had ocular and other anomalies. The elder of these (III.1, Fig 1) had unilateral cataract, global developmental delay, and similar facial features to III.3 (Fig 2C). She died age 6 years as a result of aspiration pneumonia. The other sibling (III.2, Fig 1) had cloudy corneas at birth. She died soon after birth as a result of laryngeal stenosis (Fig 2D).
Analysis of the family history revealed that the patient’s father (I.1, Fig 1), had also had juvenile onset cataracts but was otherwise well. He had two other children with ocular anomalies and mental impairment. The elder daughter (III.1, Fig 1), had juvenile onset cataracts and died age 29 years because of cardiac arrhythmia. The second daughter (III.2, Fig 1), developed cataracts in early childhood and had bilateral dense cataracts at the age of 30 years. Both these individuals had limited speech and required assistance with personal care. These women have dysmorphic facial features similar to those seen in their developmentally delayed nieces.
Karyotype analyses were requested on surviving family members. These demonstrated that the two otherwise normal men (I.1 and II.3), with juvenile onset cataracts, were carriers of the same balanced translocation 46,XY,t(5;16)(p15.3;q23.2) (Fig 1). Their two surviving offspring (II.2 and III.3) with more severe ocular anomalies, mental retardation, and dysmorphic facial features both had the same unbalanced derivative karyotypes, 46,XX,der(5),t(5;16)(p15.3;q23.2) (Fig 1). Tissue had been taken at necropsy for a karyotype analysis on III.2 which had also shown additional material on chromosome 5. This would be consistent with the unbalanced karyotype seen in her sibling, but unfortunately contact with the family about this at the time did not proceed. Karyotype analyses were not performed in II.1 or III.1 before their deaths and had not been performed in III.3 before the genetic referral.
The diagnosis of the chromosomal translocation has significant implications for management and options for individuals in this family. The indications for karyotype analysis are not specifically emphasised to ophthalmologists as this is generally not part of the ophthalmologist’s role in patient care. Nevertheless, chromosomal anomalies are frequently reported in the ophthalmic literature and contributions to identification of several genes in human eye disease, including PAX6, FOXC1, PITX2, and MAF from this family, have been made through analysis of chromosome abnormalities.1–4
In assessing the child with a congenital ocular anomaly, the presence of at least one other anomaly including another malformation or mental retardation, with or without dysmorphic features, is an indication for karyotype analysis. For the child, the finding of a chromosomal abnormality identifies the likely underlying cause, gives information regarding prognosis and directs management options. For the family, the origin of the chromosomal abnormality is critical in determining the likelihood of recurrence in a future pregnancy.
The parents of a child with a chromosome abnormality should be offered karyotype analysis. If one of the parents is a carrier of a balanced form of the translocation, this carries a risk of recurrence of up to 20% or sometimes higher of having a malformed and mentally retarded child as a result of transmission of an unbalanced chromosomal complement.5 Couples where one partner is a balanced translocation carrier can be offered prenatal diagnosis in a future pregnancy. If a parent is a balanced translocation carrier, one of his or her parents may also be a carrier so that siblings and other more distant relatives may also carry the translocation with its attendant risks for a future pregnancy. If the parental karyotypes are normal, the chromosomal abnormality has probably arisen as a de novo event in the egg or sperm that went to make that child, and the likelihood of recurrence in a future pregnancy is low. Such risk analyses vary between families depending on family history and the particular chromosomal rearrangement: referral to a clinical genetics unit for assessment is recommended.
When a patient is seen with an ocular abnormality associated with mental retardation, dysmorphic features, or another malformation, a request or referral for karyotype analysis is indicated because of the significant impact that the diagnosis of a chromosomal abnormality has for the individual and family. In this family the diagnosis of a familial chromosomal abnormality was made only recently. Before this five children were born over a period of 35 years with ocular abnormalities and associated features including mental retardation, dysmorphic features, and other non-ocular malformation, all caused by a chromosome abnormality derived from the balanced translocation in their parent.
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