Aplastic anemia, mental retardation, and dwarfism (AMeD) syndrome, also known as aldehyde degradation deficiency (ADD) syndrome, a rare genetic disorder characterized by severe clinical manifestations, including bone marrow failure, intellectual disability, short stature, and microcephaly, poses significant diagnostic and therapeutic challenges [1]. AMeD is caused by mutations in the ALDH2 and ADH5 genes, which encode the enzymes aldehyde dehydrogenase 2 (ALDH2) and alcohol dehydro-genase 5 (ADH5), respectively. These enzymes metabolize aldehydes, including formaldehyde, a known cytotoxic and genotoxic agent [1-3]. AMeD-associated mutations cause cellular accumulation of formaldehyde, subsequently impairing DNA repair mechanisms and triggering developmental and hematological abnormalities.

Recent research, including one pivotal study by Oka et al., has highlighted the digenic nature of AMeD syndrome, implicating the ALDH2 and ADH5 genes (Fig. 1) [1]. Specifically, this study identified crucial homozygous or compound heterozygous mutations in ADH5 in multiple unrelated Japanese families, further complicated by a prevalent polymorphism, rs671, in ALDH2 [1]. This mutation combination exacerbated enzymatic inefficiency, causing the cellular machinery responsible for detoxifying aldehydes to become overwhelmed.

Figure 1. Pathogenic variants identified in the ADH5 and ALDH2 genes. Whole-exome sequencing revealed compound heterozygous (c.832G>C [p.Ala278Pro] and c.678delA [p.Asp227fs]) variants in the ADH5 gene, in addition to the heterozygous pathogenic variant (c.1510G>A [p.Glu504Lys]) in the ALDH2 gene. *Denotes a novel mutation.

So far, 16 patients with AMeD have been reported, exhibiting a range of clinical symptoms [1,2,4]. The clinical presentation of AMeD syndrome shows significant variation, but typically involves bone marrow failure (mani-festing as pancytopenia), in addition to reductions in red and white blood cell and platelet counts [5]. This hematological characteristic contributes significantly to the associated morbidity. Growth retardation and neurological deficits are the hallmark features of AMeD that complicate its clinical course and require multidisciplinary care [1,2,4]. Considering the complexity and rarity of AMeD syndrome, herein we present a case of a 7-year-old girl to shed light on its nuanced presentation. This report may improve our current understanding of AMeD syndrome by exploring the genetic and phenotypic aspects of the present case, underscoring the importance of considering digenic disorders in patients with similar clinical presentations. Further, this case emphasizes the critical role of advanced genetic testing, such as whole-exome sequencing (WES), in the diagnosis of complex multisystem genetic disorders, potentially guiding targeted therapy and improving patient outcomes.

A 7-year-old girl presented to our center with multiple characteristics of AMeD syndrome, including pancyto-penia, developmental delay, microcephaly, epilepsy, and myelodysplastic syndrome. She was born prematurely at 36+1 weeks owing to intrauterine growth retardation, and was delivered via cesarean section. She exhibited low birth weight, short length, and a small head circum-ference. At 2 months of age, she experienced her first seizure, at which point an electroencephalogram indi-cated epilepsy. Brain magnetic resonance imaging (MRI) revealed bilateral pachygyria and delayed myelination (Fig. 2A), and multiple antiepileptic drugs were admini-stered.

Figure 2. Brain MRI findings. (A) Ini-tial brain MRI at age 2 months showing bilateral pachygyri with delayed myelination. (B, C) Brain MRI at age 1 year showing bilat-eral diffuse cerebral atrophy with severely delayed myelination.

During hospitalization, she had a dysmorphic face characterized by a slightly puffy appearance, a low nasal bridge, microcephaly, and pancytopenia. Her hemoglobin concentration was 8.3 g/dL, with white blood cell and platelet counts of 3,400 and 40,000 cells/mL, respectively. Initial bone marrow examinations revealed myelodysplastic syndrome (MDS) (Fig. 3), confirmed based on subsequent examinations revealing trilineage dysplasia and hypocellular marrow. Chromosomal analysis revealed 46,XX, +1,dic(1;21)(p11;q11.2)[4]/46,XX[16]. She was diagnosed with primary hypothyroidism at 12 months of age, for which thyroid hormone supplementation was initiated (free T4 0.83 ng/dL and TSH 21.96 mIU/L). Brain MRI further confirmed bilateral cerebral atrophy and a severe delay in myelination (Fig. 2B and 2C). A percutaneous endoscopic gastrostomy (PEG) was performed, considering her feeding difficulties and gastroesophageal reflux.

Figure 3. Bone marrow findings. (A) Dy-serythropoiesis (megaloblastic changes, arrows) in the bone mar-row as-pirate (×400, Wright Giemsa stain). (B) Normocellular marrow in the bone marrow biopsy (×200, hema-toxylin-eosin stain).

At 5 years of age, genetic testing using WES identified compound heterozygous variants in ADH5 (c.832G>C and c.678delA) and a heterozygous pathogenic variant in ALDH2 (c.1510G>A), which are important to understand the dysfunctional metabolism of formaldehyde, a characteristic of AMeD syndrome (Fig. 1). The ALDH2 variant occurs in 24% of East Asians, and is considered a risk factor for AMeD syndrome. The ADH5 c.832G>C variant has been previously reported [1], but the c.678delA variant is a newly identified mutation. The patient remained bedridden, was fed via PEG, and could only perform minimal movements. Hip radiography revealed a bilateral coxa valga and worsening hip subluxation, further impacting mobility (Fig. 4). Growth measurements continued to fall below the 1st percentile, and development was significantly delayed in all areas. At 7 years of age, the patient’s length and weight were 87.4 cm (−8.2 SDS) and 7.9 kg (−5.2 SDS), respectively.

Figure 4. Bone X-ray of the hip and lower extremity. Bilateral coxa valga and bilateral hip subluxation can be observed.

As of January 2024, the patient remains on anti-seizure medications and has not recently experienced any major seizures. However, persistent pancytopenia has progressively worsened, necessitating weekly platelet and biweekly red blood cell transfusions. Recent laboratory results show a hemoglobin concentration of 7.9 g/dL, with white blood cell and platelet counts of 1,620 and 7,000 cells/mL, respectively. Treatment for transfusional hemosiderosis was initiated due to frequent transfusions.

This case provides insight into AMeD syndrome, a rare genetic disorder characterized by mutations in the ALDH2 and ADH5 genes. The diagnosis of this patient was established through a combination of clinical manifestations and confirmatory tests, including bone marrow and genetic analyses. At presentation, the patient exhibited persistent pancytopenia, microcephaly, short stature, and developmental delay, prompting further investigation and ultimately leading to her diagnosis.

HSCT was considered a therapeutic option following the initial diagnosis of MDS, however, it was not pursued as the patient did not meet the standard criteria for transplantation because of concurrent neurological symptoms and developmental delays [6,7]. Instead, a multidisciplinary approach focusing on supportive care was adopted, including regular blood transfusions for pancytopenia and interventions addressing associated complications, such as feeding difficulties, gastroesophageal reflux, hypothyroidism, and hip dislocation.

The pathogenesis of AMeD syndrome stems from digenic mutations in ALDH2 and ADH5, which encode the enzymes critical for formaldehyde detoxification [1,2,5]. Enzymatic dysfunction causes formaldehyde accumula-tion, resulting in DNA damage and potential disruption of cellular functions, including hematopoiesis and neurodevelopment [8,9]. This molecular pathology of AMeD underscores the importance of genetic testing to guide diagnostic and therapeutic strategies, thereby enabling patient-specific management.

Although HSCT is regarded as a potential treatment for bone marrow failure of AMeD syndrome, the reported outcomes from previous cases have shown varying degrees of success [1,2,4]. Alternative therapeutic avenues focusing on reducing endogenous formaldehyde levels have also been proposed, but require further exploration and validation [10].

In summary, this case highlights the intricate interplay between genetic mutations, biochemical pathways, and clinical phenotypes in AMeD, underscoring the need to employ a multidisciplinary approach encompassing clinical expertise, genetic testing, and supportive care to optimize patient outcomes. Further elucidation of the underlying pathophysiology and exploration of innovative therapeutic modalities are required to advance our understanding and management of this complex syndrome.

We would like to acknowledge the contributions of professors Moon Seok Park and Ju Seok Ryu, who were instrumental in the initial design of the study and the data collection process. Although not listed as authors, their preliminary analyses and expertise were invaluable to the overall success of this report. We wish to extend our deepest gratitude for their efforts and insights.

The authors have no conflict of interest to declare.