Broad Phenotypic Heterogeneity and Multisystem Involvement in Single mtDNA Deletion-associated Pearson Syndrome

We read with interest the article by Khasawneh et al. about a 4 months-old male with Pearson syndrome due to a novel mtDNA deletion (1). We have the following comments and concerns.

The authors mention that Pearson syndrome may be due to mtDNA point mutations (1). We do not agree with this notion. If at all, this is a completely rare event. In the vast majority of the cases, Pearson syndrome is due to mtDNA deletions, which usually occur spontaneously, without germline transmission. Only in about 4% of the cases, single mtDNA deletions are inherited from the mother’s side (2). Duplications are also a rare event, but may occur more frequently than point mutations (3, 4).

With regard to the phenotype of Pearson syndrome, it has to be stressed that it is not confined to the bone marrow and the pancreas as originally reported, but is in fact a multisystem disease (Table 1) (5). Affected organs other than the bone marrow and the pancreas include the kidneys (Fanconi syndrome (glucosuria, hyperphosphatemia, proteinuria, aminoaciduria), renal insufficiency, global sclerosis of glomerula, 3-methyl glutaconic aciduria (6), tubulopathy and tubular atrophy) (5), the liver (steatosis (6), liver dysfunction (6), hepatomegaly (6), or vacuolated hepatocytes) (6, 7, 8), the central nervous system (seizures, ataxia, retarded speech development, muscle hypotonia, hypointensities of the brain stem, or subcortical white matter lesions with white or grey matter lesions (9), or as movement disorders, particularly tremor) (9), the eyes (retinal or corneal compromise (9), corneal endothelial dysfunction) (8), the endocrine organs (growth retardation with short stature, diabetes, hypoparathyroidism (9), or adrenal insufficiency) (10), the heart (myocardial thickening, repolarisation abnormalities, QT-prolongation, bicuspid right ventricle (9), or as complex–IV deficiency) (6), the blood (anemia, leucopenia, thrombocytopenia, acute myeloid leukemia) (9), the skin (focal hyperpigmentation, café aux lait spots (9), or as cutaneous zygomatosis (11)), the gastro-intenstinal tract (duodenal ulcer, diarrhea (12, 13), reflux, or malabsorption (Table 1), the skeletal muscle (ptosis, muscle weakness, or myopathy (6)), or other abnormalities (e.g. splenomegaly (9)).

Table 1. Phenotypic manifestations of patients with Pearson syndrome.

Organ/tissue	Abnormality	Frequency	Reference
Central nervous system
	Epilepsy	+	[12]
	Ataxia	+	[14]
	Movement disorder (tremor)	+	[14]
	Hypotonia	++	[15]
	Failure to thrive	++	[15]
	Diffuse white matter lesions	+	[15]
	Subcortical white matte lesions	+	[9]
	Delayed motor milestones	++	[14,15]
	Attention deficit	+	[12]
	Hypomyelination (PLIC)	+	[15]
	Leigh-like features	+	[9,16]
	Hypointensities of brain stem, cerebellum, pons	+	[9,14]
	Cortical blindness	+	[12]
	Cerebral atrophy	+	[12]
	Basal ganglia calcification	+	[14]
	Lactic acidosis	+++	[15]
Peripheral nervous system
	Myopathy	+	[6]
	Ptosis	+	[13]
	Absent deep tendon reflexes	+	[15]
Eyes
	Corneal opacities	++	[8,9,17]
	Retinal compromise	+	[9]
Endocrine organs
	Diabetes	+++	[5]
	Growth retardation (short stature)	+++	[9,13,15]
	Adrenal insufficiency	++	[10,17]
	Hypoparathyroidism	+	[9]
Heart
	Complete heart block	+	[18]
	Right (left) myocardial thickening	+	[9,13,15]
	Repolarisation abnormalities	+	[9]
	QT-prolongation	+	[9]
	Bicuspid right ventricle	+	[9]
Gastrointestinal
	Exocrine pancreas insufficiency	+++	[15]
	Steatosis	+++	[16]
	Hepatomegaly	++	[15]
	Malabsorption	++	[15]
	Liver dysfunction	+++	[6,8]
	Vacuolated hepatocytes	+	[6]
	Reflux	++	[15]
	Duodenal ulcer	+	[12]
	Diarrhoea	++	[12]
Kidneys
	Renal cysts	+	[19]
	Tubulopathy	+++	[5]
	Fanconi syndrome	++	[6]
	Renal insufficiency	+	[6]
	Global sclerosis of glomerula	+	[6]
Blood
	Anemia	+++	[9,13]
	Leucopenia	+++	[9]
	Thrombocytopenia	+++	[9]
Skin
	Hyperpigmentation	+	[9]
	Café au lait spots	+	[9]
Other
	Hypospadia	+	[20]
	Cleft lip/palate	+	[20]
	Serum lactate ↑	+++	[15]
	Urine organic acids ↑	++	[15]
	3-methly-glutaconic aciduria	++	[6]
	Splenomegaly	+	[9]
	Acute myeloid leukemia	+	[9]

Since most organs can be clinically or subclinically affected in Pearson syndrome (Table 1), it is essential to investigate patients with Pearson syndrome prospectively for central nervous system involvement, endocrine abnormalities, kidney disease, cardiac compromise, renal disease, skin abnormalities, gastrointestinal compromise, myopathy, and for ophthalmologic disease. Were prospective investigations for subclinical disease in any organ/tissue in the described patient carried out, and were any phenotypic manifestations in addition to bone marrow dysfunction and pancreas insufficiency detected as listed in Table 1?

The patient is reported to have had developed hepatomegaly (1), which has been only rarely previously reported (Table 1). Was hepatomegaly due to primary hepatic compromise or secondary due to heart failure? Heart failure cannot be excluded since the presented patient had been admitted for dyspnea and cyanosis (1). Which were the ECG and echocardiographic findings?

Overall, this interesting report could benefit from provision of prospective investigations for multiorgan involvement, and a comprehensive discussion of previously reported data, including the broad phenotypic heterogeneity between patients.

Conflict of interest:

There are no conflicts of interest

Author’s contribution:

All authors contributed equally in design, literature search, discussion, first draft.

Competing interest:

No funding was received..

Declaration of patient consent:

Authors certify that they have obtained patient consent form.