Diagnosing Pearson syndrome requires proving a single mtDNA deletion

Letter to the Editor,

We read the article by Faisal et al. with interest, which reports on a Pakistani male infant born to consanguineous parents and diagnosed with Pearson syndrome due to the clinical presentation (short stature, low body weight, hypotonia) as well as laboratory findings (pancytopenia, anisopoikilocytosis with cytoplasmic vacuolization of erythroid precursors, exocrine pancreatic insufficiency, and steatosis) [1]. The patient had five siblings, three of whom died early, and one had megaloblastic anaemia. It was concluded that Pearson syndrome should be considered in infants with unexplained pancytopenia, multisystem involvement, and a family history suggestive of Pearson syndrome [1]. The study is forward-looking, but some points should be discussed.

The first point is that the diagnosis of Pearson syndrome is questionable. Since the diagnosis wasn’t confirmed by documenting a single mitochondrial DNA (mtDNA) deletion and because pancytopenia with vacuolated precursor cells can also be associated with other diseases [2], it would have been essential to test the mtDNA for a single mtDNA deletion to confirm Pearson syndrome. Also, hypotonia and liver steatosis are not clear diagnostic criteria for Pearson syndrome. Generally, mitochondrial disorders (MIDs) should not be diagnosed without genetic confirmation [3].

The second point is that even close first-degree relatives weren’t tested for mtDNA mutations. Since three siblings died in infancy and one sibling had megaloblastic anaemia, and because single mtDNA deletions can be rarely passed down through the maternal line [4], it would have been crucial to test other first-degree relatives. Megaloblastic anaemia in a sister of the index case suggests that the disease was passed from the mother to both children. Were any other first-degree family members genetically tested for the presence of an mtDNA deletion? Was a mutation in a nuclear gene considered as the cause of the disease? Since the parents are related, it’s also important to test the patient and his parents for chromosomal defects.

The third point is that the index patient was not prospectively examined for subclinical multisystem disease. Since Pearson syndrome can develop into Kearns-Sayre syndrome (KSS) over time [5], it is crucial that patients with Pearson syndrome are checked for subclinical signs of multisystem involvement, just like in KSS. The earlier the involvement of other organs besides the bone marrow and pancreas is detected, the earlier and more effectively symptomatic treatment can be started.

The fourth point is that we do not agree with the view that the patient's small size is due to failure to thrive [1]. A possible explanation other than malnutrition could be a hormonal imbalance, particularly a deficiency in somatotropin due to involvement of the endocrine system. Endocrine system involvement has already been described in Pearson syndrome and also includes hypopituitarism [2]. Since the patient has also presented with short stature and underweight, it would have been helpful to measure all hormone levels.

The fifth point is that we disagree with the statement that slightly elevated HbA1c levels are nonspecific [1]. Abnormal glucose metabolism warrants further evaluation for endocrine involvement, including an oral glucose tolerance test. Since Pearson syndrome is a classic syndromic MID and MIDs can be complicated by lactic acidosis, the lactate level in the serum and cerebrospinal fluid should have been measured. Was the blood gas analysis indicative of acidosis?

Abbreviations

KSS

Kearns–Sayre syndrome

MID

Mitochondrial disorder

MtDNA

Mitochondrial DNA

Author contributions

JF: was responsible for all aspects.

Funding

No funding was received.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Consent for publication

Not applicable.

Competing interests

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.