Variant ataxia telangiectasia identified during evaluation for short stature

Abstract

Ataxia telangiectasia (A-T) (OMIM 208900) is an autosomal recessive multisystem disorder characterised by progressive cerebellar ataxia, telangiectasias, immunodeficiency and a predisposition to malignancy. ‘Variant’ A-T has later onset of neurological symptoms and slower progression compared with the ‘classic’ form. A woman presented with short stature in late childhood. Karyotype revealed rearrangements involving chromosomes 7 and 14. A chromosomal breakage disorder gene panel demonstrated compound heterozygote mutations in her ATM gene including one mutation c.7271T>G with residual ATM function, confirming the diagnosis of variant A-T. Since diagnosis, she has developed progressive cerebellar ataxia and telangiectasias. Long-standing restrictive and aversive feeding behaviours presented challenges for her management and necessitated gastrostomy.

Background

Ataxia telangiectasia (A-T) (OMIM 208900) is an autosomal recessive multisystem disorder with a widely varied phenotype. It is characterised by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, a predisposition to malignancy, sensitivity to ionising radiation and chromosomal breakage. A-T is the result of homozygous or more frequently, compound heterozygous pathogenic variants in the ATM gene on chromosome 11q22.¹ The prevalence is estimated to be between 1 in 40 000 and 100 000 live births.² Carrier frequency for pathogenic ATM alleles is estimated to be between 1.4% and 2%.³ An increased risk of malignancy and coronary artery disease is observed in carriers.

‘Classic’ and ‘variant’ forms are described but are somewhat ill defined. A recent review noted just 2.5% of included cases were variant A-T.⁴ From a genetic perspective, the classic form is associated with the absence of ATM protein or kinase activity, whereas variant forms are typically compound heterozygotes with one mutation facilitating some preservation of ATM function. The median age at diagnosis for classic and variant forms is 6 and 29 years, respectively.⁴ The most common presenting symptoms in both are gait abnormality or recurrent infections. This heralds immunodeficiency, however, this is not always the case. In classic A-T, early childhood progressive cerebellar dysfunction develops in the first 2 years of life with onset of telangiectasias in the preschool years. The median age of wheelchair use and death is 10 and 14 years of age, respectively. In contrast, neurological symptoms in variant forms manifest in later adolescence and early adult life with a median age of death of 48 years.

Disordered growth and short stature are recognised features of both forms but are rarely the presenting complaint. We present a case of variant A-T identified during investigation of short stature, before the onset of neurological symptoms or oculocutaneous telangiectasias.

Case presentation

The proband was born at full term, weighing 2.8 kg to non-consanguineous parents. She was referred to general paediatric outpatients in her mid-childhood for recurrent urinary tract infections, consequent to dysfunctional voiding behaviours. She had a history of mild asthma which was well controlled on low-dose beclomethasone and montelukast. Cardiovascular, respiratory and abdominal examinations were normal. She had no neurological symptoms or neurocutaneous stigmata.

At the clinic, her height and weight were on the 0.4th centile (−2.5 SDs) compared with a mid-parental height between the 50th and 75th centiles. There was a family history of coeliac disease in a maternal first-degree relative. Maternal age at menarche was 12, however, her father reported to have completed growth between the ages of 19 and 20, suggesting constitutional delay of growth and puberty. Her height when plotted for her bone age was on the ninth centile. Growth velocity remained normal until adolescence when it began to slow, which was felt to be consistent with the absence of clinical onset of puberty. Her parents were concerned that she was the smallest in her school class, despite being the oldest. Investigations were, therefore, undertaken. Spontaneous onset of puberty (Tanner stage 2 breast development) occurred just prior to her 13th birthday; the accepted sex-specific age threshold for delayed puberty.

Treatment

The proband is linked to general paediatrics, respiratory, immunology and neurology in addition to physiotherapy, occupational therapy, speech and language therapy, psychology and dietetics. She has also attended a specialist multidisciplinary clinic for patients with A-T. She is on vitamin D 400 units daily and melatonin as required for difficulties with sleep initiation. Due to concerns regarding poor weight gain, a long-standing restrictive pattern of eating, aversion to oral nutritional supplementation and difficulties taking oral medications, a percutaneous enteroscopic gastrostomy (PEG) tube was placed.

Outcome and follow-up

In late adolescence, she is under multidisciplinary care including being linked to a specialised A-T multidisciplinary clinic.

Neurology

Neurological symptoms manifested in mid-adolescence and initially consisted of intermittent tremor and mild truncal ataxia. Now in late adolescence, there has been an objective decline in neuromuscular function. She can walk 20 m unaided and for between 2 and 3 min with assistance. Fatigue has been a significant contributor to her functional decline and is currently sleeping for 11 hours per day. She tolerates two half days per week of home schooling.

Endocrinology, growth and nutrition

Pubertal onset occurred as she approached her 13th birthday. Menarche occurred 2.5 years later. She had significant menorrhagia, and due to her inability to take medication in tablet form, she was commenced on a transdermal ethinyloestradiol/norelgestromin patch and counselled appropriately. Final adult height is 155 cm (9th centile) and current weight is 49.2 kg (9th–25th centile). She has gained 12 kg since insertion of her PEG tube and her nutritional status is now adequate.

Immunology

IgA deficiency is present, however, no other significant immune deficits have been identified. She has no history of frequent, unusual or severe infections. She receives annual influenza vaccine and has had pneumococcal booster vaccination. She is not on any antibiotic prophylaxis.

Malignancy

There has been no evidence to date, and she has been counselled regarding possible signs and symptoms of concern.

Genetics

The family has been reviewed by clinical genetics and by genetic counsellors. Mum has been advised of the need to undergo screening mammography from the age of 40 and to undertake regular breast self-examination. Screening of female first-degree relatives on her father’s side has been suggested; this is of particular importance her father carries the higher risk c.7271T>G variant.

Transition to adult services is in progress.

Discussion

A-T is caused by pathogenic variants in the ATM gene, responsible for maintaining genomic stability by coordinating DNA-damage response and regulating cell-cycle damage/progression checkpoints.⁵ Classic A-T is associated with shift or nonsense mutations causing truncation of the transcript and undetectable ATM protein or kinase activity⁶ . Selected missense, leaky splice-site and one-in-frame mutations produce some functioning ATM protein resulting in a milder variant phenotype.⁷ Our patient had one missense variant [c.7271T>G], which allowed for reduced but active ATM protein explaining the later onset neurological symptoms.⁸

Poor growth is a recognised feature of classic A-T and many of those affected have short stature and failure to thrive.⁹ There is a correlation between height centile and longevity in A-T. Notwithstanding this, a recent systematic review demonstrated that poor growth was rarely the presenting complaint in classic and even more rarely or not at all in the variant form.⁴ Poor growth is recognised in utero and individuals with classic A-T have lower birth weights than the variant subtype (median birth weight 27th vs 61st centile).⁹ Postnatal factors potentially impacting growth include, recurrent infections, IGF-1 deficiency and reduced nutrient intake due to fatigue and difficulty swallowing. A recent study⁹ showed that the impact of classic A-T on height and weight-gain in women was greater. The median height reaches the third centile on the Centers for Disease Control and Prevention growth charts by the age of 6 in women and age 16.5 in men. Women crossed below the third centile at the age of 11.5, whereas men did not fall below. Height more than 2 SDs below the mean occurred in 67% of women and 41% of men with classic A-T compared with 4% with variant A-T. Sex-specific height differences also occur in the variant form, but data are limited. In this case report, height was on the 0.4th centile at the time of initial review and dropped below subsequently. Final adult height was on the 9th centile compared with a mid-parental height between the 25th and 50th. From the literature, the median height in variant A-T is between the 25th and 50th centiles compared with the 9th centile in those with classic A-T. Failure to thrive is not reported to occur in variant A-T, however, in this case, weight fell below the 0.4th centile before reaching the 9th centile post-PEG insertion. Some authors have suggested proactive PEG placement from the age of 8 in the classic form to mitigate growth faltering,¹⁰ however, a more recent review did not demonstrate statistically significant difference in BMI in those with or without PEG tubes, although this was based on retrospective data.⁹ A small study of 10 patients with A-T found that almost 60% had a disturbance of the Growth Hormone/Insulin like growth factor-1 axis,¹¹ however, concerns exist regarding use of growth-promoting agents in patients with chromosome breakage disorders. Our patient had normal GH secretion prior to her diagnosis so GH use was not a consideration.

A-T patients have an increased risk for developing malignancies, with an incidence estimated to be 10%–20% in the classic form.¹² Excess malignancy associated with carrying the c.7271T>G variant is particularly noteworthy as it appears to be the variant associated with the highest risk in carriers. The cumulative incidence of female breast cancer by age 70 in c.7271T>G carriers is estimated to be between 50% and 60%.¹³ The risk is estimated to be like that for BRCA2 mutations and it has been recommended that this is reflected in screening advice.¹⁴ In this case, the c.7271T>G variant was paternally inherited, which although associated with increased malignancy risk relative to the background population, is somewhat lesser consequence in a man. Familial testing for this variant in female first-degree relatives has been advised.

Variant A-T may rarely, as in this case, present with short stature in the absence of neurological signs or oculocutaneous telangiectasias. A genetic diagnosis is essential as specific mutations such as c.7271T>G confer an additional malignancy risk in carriers, over and above that seen with other mutations and may merit specific screening, particularly in women.

Learning points.

• During investigation of short stature, in addition to identifying Turner syndrome, karyotype can also provide evidence of chromosome breakage disorders.

• Short stature is common in ‘classic’ ataxia telangiectasia (A-T) and this phenotype is more evident in women.

• Short stature is rarely the presenting complaint, particularly in variant A-T.

• Percutaneous enteroscopic gastrostomy insertion was associated with an improvement in growth parameters in our case, however, there is insufficient evidence to support its universal application in A-T patients.

Ethics statements

Patient consent for publication

Consent obtained from parent(s)/guardian(s).