Kearns-Sayre syndrome presenting as isolated growth failure

Abstract

Failure to thrive arises from a heterogeneous group of paediatric disorders including defects in energy metabolism such as mitochondrial diseases. Illustrating this, we describe a girl with poor growth who eluded diagnosis until she developed characteristics of Kearns-Sayre syndrome. Her history emphasises that defects of energy metabolism can present as isolated growth failure.

Background

Growth is a fundamental characteristic of childhood and a sensitive indicator of nutritional status. From fertilisation to adulthood, growth can be divided into the periods of intrauterine, infancy, childhood and puberty.¹ Recognising growth and developmental problems in infants and children are common challenges for paediatricians.

Failure to thrive (FTT) can be characterised by a weight and/or height drop of 2 SD, weight and height less than the fifth centile, body mass index (BMI) less than the fifth centile, weight less than the 75th centile for age or weight less than the 75th centile for length.² It is based on population-matched, gender-matched and age-matched healthy individuals and can be caused by nutritional or psychosocial deprivation, chronic diseases, inborn errors of metabolism, food allergies and/or hypothyroidism.²

Disorders of energy metabolism are a class of diseases in which affected individuals frequently exhibit poor growth.^{3 4} For example, 38% of individuals with Kearns-Sayre syndrome (KSS), a multisystem mitochondrial disorder, have short stature.⁵ KSS, which has an estimated prevalence of 1–3/100 000,⁶ is classically characterised by chronic progressive external ophthalmoplegia before 20 years of age, retinal pigmentary degeneration and at least one of the following signs: cardiac conduction defect, cerebellar ataxia or elevated cerebrospinal fluid protein concentration (>100 mg/dl).^{7 8} KSS arises from mitochondrial DNA (mtDNA) deletions that lead to impaired oxidative phosphorylation and reduced ATP production.⁹

Two nonexclusive theories have been proposed for the mechanism by which mitochondrial cytopathies such as KKS result in growth failure. The first proposes that reduced ATP production impedes hypertrophy and hyperplasia of growth plate chondrocytes autonomously.¹⁰ The second proposes that reduced ATP production impedes production and excretion of hormones required for growth such as growth hormone (GH).^{3 11} The frequent identification of hormone deficiencies among patients with mitochondrial cytopathies supports the latter proposal; among KSS patients for example, 6% have hypoparathyroidism, 20% hypogonadism, 13% hypoinsulinism and 3% hypothyroidism.⁵

To highlight the need to consider mitochondrial diseases as a cause of growth failure, we report a girl who presented with poor growth 2 years prior to developing symptoms suggestive of mitochondrial disease and 4 years prior to developing signs diagnostic of KSS. Similar to some other KSS patients,^{12 13} her growth improved minimally with growth hormone supplementation.

Case presentation

The proband was an 11-year-old girl who presented to the Undiagnosed Diseases Program at the National Institutes of Health with postnatal growth failure, chronic fatigue, hypothyroidism, progressive ptosis, optic atrophy and retinitis pigmentosa (figure 1). She was the third child of non-consanguineous healthy parents; no other family members had similar problems. Her parents gave written, informed consent under the protocol #76-HG-0238, 'Diagnosis and Treatment of Patients with Inborn Errors of Metabolism and Other Genetic Disorders’.

Figure 1.

Clinical and retinal photographs. (A) Facial photograph illustrating ptosis. (B) Facial photograph illustrating disconjugate gaze as a manifestation of the external ophthalmoplegia (C–D) Photographs of the right (C) and left (D) retina. Widening of the optic cup indicates myelin shrinkage and optic atrophy and isolated pigmented spots indicate peripheral retinal degenerative changes.

The proband was born at 36 weeks’ via caesarean section following an uncomplicated pregnancy. Birth weight was 3685 g. She had normal prenatal and early postnatal growth and achieved developmental milestones appropriately. However, her weight gain and linear growth began to slow down between 3 and 5 years; at 5 years, her length, which was at the 75th percentile at birth, was <3rd percentile with a BMI at the 25th centile and a weight for length at the 25th–50th centile (figure 2). An evaluation for growth failure revealed delayed bone age, normal GH levels and a normal GH stimulation test. Nonetheless, she was given a trial of GH supplementation and her growth improved slightly.

Figure 2.

(A) Length-to-weight for 0–36 months, (B) stature-to-weight growth charts for 2–20 years (C) BMI-to-weight for 2–20 years (D) stature-to-weight only. Notice the birth weight at the 75th percentile and the decline in weight and height between 3 and 5 years to less than the third percentile.

While being evaluated for growth failure, the patient developed additional problems. At 7 years, she had difficulty swallowing, fatigue causing sleepiness in school and memory problems such as difficulty with letter recognition. By 9 years, she had bilateral ptosis, dysphagia, proximal weakness, ataxia, constipation and retinal degeneration. At 10 years of age, testing for the common mutations of MERRF (Myoclonic Epilepsy with Ragged Red Fibers) and MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes) were negative. However, her BMI and weight for height dropped to less than the fifth centile (figure 2).

The physical examination of the 11-year-old exhibited proportional growth restriction and normal vital signs. Her neurological examination was remarkable for bilateral ptosis, right-sided exotropia, pes planus and mild gait instability. Although she did not complain of poor vision, her ophthalmologic exam showed signs of external ophthalmoplegia, retinitis pigmentosa and optic atrophy (figure 1).

Investigations

Laboratory evaluations revealed thrombocytopenia but otherwise normal blood cell counts and normal levels for iron saturation, non-fasting and fasting glucose, glycated haemoglobin (HbA1c), lactate and pyruvate. Plasma alanine was 631 µmol/l (88–440 µmol/l), FSH was 1.5 mlU/ml (1.8–3.2 mlU/ml) and free testosterone was 0.1 ng/dl (0.3–19 ng/dl). Her cerebrospinal fluid contained 152 mg/dl protein (15–45 mg/dl), 71 mg/dl glucose (40–70 mg/dl) and 4.7 nmol/l lactate (0.7–2.2 nmol/l). Nerve conduction studies identified peripheral neuropathy. A DEXA scan of her left forearm showed normal bone density.

Differential diagnosis

The patient's clinical features of ptosis, retinitis pigmentosa, optic atrophy, hypothyroidism, dysphagia, growth failure, ataxia, peripheral neuropathy and elevated CSF protein and lactate levels suggested a disorder of energy generation, particularly the mitochondrial disorders MELAS and KSS. Given her previously negative testing for MELAS and MERRF and the presence of external ophthalmoplegia, retinal pigmentary degeneration, and a CSF protein concentration >100 mg/dl, we hypothesised that she had KSS. Confirming this diagnosis, mitochondrial DNA (mtDNA) deletion testing on whole blood identified a 3.9 kb deletion (base pairs 8404 to 12385). This deletion removes several genes encoding protein subunits for electron transport complexes I and V and an assembly factor for complex IV.

Treatment

After the diagnosis of KSS, the patient's growth hormone supplementation was discontinued since it had little impact on her overall predicted adult height and could increase energy demand by stimulating cellular proliferation.¹⁴ To ameliorate her mitochondrial dysfunction, she was initially prescribed a cocktail of vitamin cofactors to optimise mitochondrial function and to encourage adherence of a pre-adolescent patient anxious to appear normal to her peers. This cocktail included ubiquinol 100 mg (three times daily), vitamin E 400 IU (once daily) and creatine monohydrate powder 5 g (twice daily as needed in times of illness or extreme fatigue). The ubiquinol was given to minimise any redox block between complexes I and II or III.¹⁵ The vitamin E was prescribed with the objective of scavenging oxygen-free radicals arising from mitochondrial dysfunction, and the creatine was given to improve muscle function through increasing muscle phosphocreatine content.¹⁵

Outcome and follow-up

Despite the above therapeutic interventions, the patient continued to grow poorly and complained of heat intolerance and fatigue. At the ages of 11 and 12 years, respectively, she developed a metabolic stroke and right bundle branch block (RBBB). The RBBB was treated with a transvenous dual-chamber pacemaker.

Given the progression of her disease as well as her persistent CSF lactic acidosis, her therapy was adjusted to include two other cofactors that ameliorate mitochondrial disease symptoms: α-lipoic acid (300 mg twice daily) and carnitine (300 mg, twice daily). α-Lipoic acid is a cofactor of the pyruvate dehydrogenase complex (PDHC) and by improving PDHC function lowers plasma lactic acid levels.¹⁵ Carnitine functions both as an antioxidant and as a covalent acceptor of organic acids; the latter facilitates excretion of excess organic acids that accumulate from poor mitochondrial function.¹⁵ In addition, her diet was supplemented with selenium and zinc based on low plasma taurine 42 (55–204 µmol/l) and zinc 61 (66–110 µg/dl) levels. Within 3 months, she had less fatigue, greater strength, improved weight gain, more tolerance for cold and warm temperatures, increased sweating and an improved sense of well-being.

Discussion

Kearns-Sayre syndrome (KSS), first described in 1958, is characterised by the clinical triad of (1) onset before 20 years of age, (2) chronic progressive external ophthalmoplegia and (3) retinitis pigmentosa. Additional features may include growth failure, heart block, sensorineural deafness, myopathy, dementia and endocrine disorders such as diabetes mellitus, hypoparathyroidism and hyperaldosteronism.⁸ Cardiac conduction defects cause syncope and heart failure in up to 57% of KSS patients and play a role in the mortality of ∼20% of these patients.⁸

KSS is typically associated with a large, single mtDNA deletion that is neither maternally inherited nor transmitted but that arises sporadically. The deletions vary in size and location in the mitochondrial genome, although a third of those affected with KSS have a common 4977 bp deletion.⁷ Since mitochondria are randomly distributed between daughter cells during cellular division, daughter cells can have mutant or wild-type mtDNA alone (homoplasmy) or a mix of mutant and wild-type DNA (heteroplasmy). In heteroplasmic tissues, the phenotype reflects the degree of mitochondrial dysfunction and is generally proportionate to the amount of mutant mtDNA, the threshold effect.⁷ Mitochondrial dysfunction causes impaired energy production as well as oxidative damage to DNA, protein and lipids. Ultimately, these problems cause cellular loss via apoptosis and necrosis.¹⁶ The mtDNA deletions and rearrangements causing KSS are generally present in all tissues but often preferentially cause disease in those that have high aerobic metabolism, for example, neurons and muscles.⁷

Although the proband ultimately developed neuromuscular problems, her presenting symptom was deceleration of growth at age 5 years (figure 2). Even though mitochondrial cytopathies are not a common cause of growth failure, poor growth is a relatively common feature of some mitochondrial cytopathies. Short stature occurs in 55% of individuals with MELAS syndrome and 36–38% of individuals with KSS.⁵ Consideration of mitochondrial cytopathies as a cause of poor growth can help avoid a long-diagnostic odyssey and period of uncertainty.^{2 5}

The cause of the poor growth in KSS is not fully understood although various observations suggest that it arises from endocrine deficiencies and induction of cell death. Currently, there is no curative treatment for the poor linear growth or most other symptoms of KSS.

Various empiric interventions have been used in the treatment of mitochondrial diseases. Dietary and pharmacological agents include creatine monohydrate (CrM) (alternative energy source and antioxidant), α-lipoic acid (antioxidant and CrM uptake enhancer), vitamin C, E and K (antioxidants), lutein, selenium (antioxidant) and coenzyme Q10 (antioxidant and bypass supplement for defected complex I).¹⁷ One study showed that a combination therapy with CrM, coenzyme Q₁₀ and α-lipoic acid significantly improved resting plasma lactate concentrations, body composition, ankle dorsiflexion strength and oxidative stress compared to placebo treatment.¹⁸ Exercise improves endurance, peak work capacity and oxygen utilisation and extraction and thereby slows or reverses the deconditioning that occurs in patients with mitochondrial disease.¹⁹ In addition, resistance training is hypothesised to decrease the load of mutant mtDNA by stimulating satellite cells to replace or repair the muscle fibres damaged by the exercise.¹⁹

In summary, patients with mitochondrial dysfunction can present with isolated growth failure and not develop symptoms characteristic of mitochondrial disease until years later. Making an early diagnosis is essential to bringing closure to testing for possible aetiologies of failure to thrive, providing prognostic and reproductive guidance, and although not curative, initiating therapies that maximise mitochondrial function and thereby the patient's quality of life.

Learning points.

• Mitochondrial disease can present as poor growth and should be included in the differential diagnosis.

• Optimising mitochondrial function with ‘mito-cocktail’ supplements can improve the sense of well-being among patients with mitochondrial disease.

• Consideration of genetic aetiologies for poor growth can facilitate diagnosis and subsequent prognostic and reproductive guidance.