Neutrophils and Lymphocytes With Characteristic Alder-Reilly Anomaly: Clues to the Diagnosis of Maroteaux-Lamy Syndrome

Abstract

Mucopolysaccharidosis type VI (MPS VI), also known as Maroteaux-Lamy syndrome, is a rare lysosomal storage disorder, characterised by a wide syndromic manifestation involving skeletal abnormalities, including short and wide thorax, macrocephaly, characteristic facial features and short limbs, hepatosplenomegaly, facial dysmorphism, and neurodevelopmental delay [1, 2]. As is well known, one of the morphological features of mucopolysaccharidoses is the occurrence of numerous, large discrete metachromatic granules in leukocytes and often with a clear zone around them, also known as Alder-Reilly anomaly [3]. Here, we describe a 7-year-old boy diagnosed as Maroteaux-Lamy syndrome, showing typical skeletal abnormalities and facial dysmorphism, as well as the presence of characteristic Alder-Reilly anomaly in the peripheral blood smears.

A 7-year-old boy was admitted because of recurrent cough for 30 days. A complete blood count revealed white blood cells 6.73 × 10⁹/L with 51.7% lymphocytes, haemoglobin 139 g/L, and platelets 404 × 10⁹/L. Physical examination revealed short-trunk short stature, macrocephaly, coarse facies, depressed nasal bridge, and bulging forehead. Peripheral blood smear showed 36% neutrophils, 52% lymphocytes, 8% monocytes and 4% eosinophils. Of note, many lymphocytes (Figure 1A–C) and neutrophils (Figure 1D–F) showed numerous intense azurophilic granules surrounded by clear halos, consistent with Alder-Reilly anomaly. The presence of these unique granules in the leukocytes raised a suspicion of Alder-Reilly anomaly and underlying MPS. Then, genetic sequencing was performed immediately by peripheral blood samples from this patient and his parent. ARSB [c.1197C<G (p.F399L)] mutation was detected from the child and his father by whole exon sequencing. Haploidy deletion in the exon 2–3 region of the gene was present in the boy and his mother. All these findings confirmed the diagnosis of Maroteaux-Lamy syndrome.

Maroteaux-Lamy syndrome is an autosomal recessive lysosomal disorder caused by the deficiency of the enzyme arylsulfatase B, leading to the accumulation of dermatan sulfate in tissues. Morphologically, one of the most characteristic features of this rare disease is the presence of abundant dark lilac granules within neutrophils, lymphocytes and monocytes, with clear halos surrounding the granules. The granules in Alder-Reilly anomaly should be differentiated from toxic granulations, granulocyte colony-stimulating factor effect and Chediak-Higashi granules [3]. The toxic granules are often found in patients with sepsis, toxic conditions, or growth factor therapy, showing larger granules that are increased in number but lacking surrounding halos. They can also be distinguished from Alder-Reilly anomaly by the presence of accompanying immature myeloid cells and the absence of granules in lymphocytes. Compared to Alder-Reilly anomaly, Chediak-Higashi, as an immunodeficiency disorder with hypopigmentation, recurrent infections, bleeding diathesis and photosensitivity, showed the presence of granules in leukocytes that are larger and lesser in number. Furthermore, neutrophils with Alder-Reilly anomaly function normally, while neutrophils in Chediak-Higashi are functionally defective, with increased susceptibility to various infections.

Notably, in addition to Maroteaux-Lamy syndrome, the Alder-Reilly anomaly can also be seen in other types of mucopolysaccharidosis, such as Morquio's syndrome [3] and Sanfilippo syndrome [4]. Moreover, this anomaly can not only occur in the peripheral blood samples but also in less commonly cerebrospinal fluid [5]. Therefore, the Alder-Reilly anomaly could serve as a morphological indicator for the differential diagnosis of mucopolysaccharidosis. This case also reminds us to keep a keen eye on physical examination, as certain physical signs are correlated closely to some rare genetic diseases. In brief, a combination of morphological examination, physical examination and genetic testing (such as whole exon sequencing) might play a critical role in the workup of congenital defects or hereditary disorders.

All authors contributed to the paper conception and design. Clinical and histological data were collected by Lingrong He, Hongjuan Yu, Xiepeng Lu and Junge Zhang. The draft of the manuscript was written by Fang Long and Ting Li, and all authors read and approved the final manuscript.

This article does not contain any studies with human participants or animals performed by any of the authors.

The authors declare no conflicts of interest.