Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods

In clinical training, clinicians are traditionally oriented toward identifying a single explanation for the clinical presentation of a patient. The concept of multiple genetic diseases in a single patient is perceived as complex and challenging [1]. Conventionally, clinicians abstract a specific phenotype to recognize Mendelian disease patterns, forming the basis for adequate diagnosis. Clinical attributes not aligning with this genetic etiology pattern may be considered phenotypic expressions. However, literature reports several cases of co-occurring genetic disorders [2‐4]. Posey et al. indicated that the occurrence of molecular “double trouble” is not as rare as previously assumed, suggesting up to 7% patients diagnosed by whole-exome sequencing possess a dual or triple genetic diagnosis [2]. This challenges the hypothesis that a single diagnosis concludes genetic investigations. Complete diagnosis in such cases is challenging, as distinguishing whether atypical clinical features represent a novel primary disease phenotype or a second genetic or acquired disease poses difficulty.

Herein all five patients exhibited clinical features that overlapped with their primary diagnoses. However, the presence of atypical clinical features prompted secondary diagnoses. For instance, in Case 1, a distinctive giggle and general developmental delay could be attributed to Angelman syndrome, but irritability and skeletal/muscle presentations were untypical. In addition to Angelman syndrome, whole-exome sequencing and CNV analyses identified a compound heterozygous variant in the GALC gene; moreover, a significant decrease was observed in galactose cerebrosidase activity. These findings confirmed the diagnosis of Krabbe disease. Similar methods were applied in Cases 2, 3, and 4 for addressing non-specific presentations. As indicated in Table 1, the examination of a secondary disease for atypical features of the primary disease was systematically initiated. In Case 5, however, because of a variation in clinical symptomatology and a less specific physical assessment, secondary disease examination was relatively complex. At 3 months of age, Case 5 presented with feeding difficulties, diarrhea, metabolic acidosis, and psychomotor retardation following vaccination against polio. Elevated levels of urine methylmalonate and methylcitrate were observed, while total homocysteine level was normal. The diagnosis of isolated MMA was confirmed by Sanger sequencing of the MMUT gene. Clinical condition of this patient improved post-treatment. The emergence of precocious puberty at age 5 raised questions about whether it represented a new phenotype of isolated MMA or resulted from a second genetic or acquired disease. To address this, whole-exome sequencing was employed for a second diagnosis, confirming 21-hydroxylase deficiency. The significance of conducting accurate diagnoses is paramount for patients, families, and caregivers as precise diagnosis offers insights into patient condition from the perspective of natural history and prognosis, enabling the application of tailored therapeutic strategies. In the context of genetic conditions, this also ensures the provision of genetic counseling. When faced with an indistinct phenotype or possibility of various etiologies, comprehensive investigations become imperative. Employing advanced genome-wide techniques, such as chromosomal microarray analysis, can facilitate CNV identification; moreover, whole-exome sequencing can be applied to detect mutations in protein-coding genes.

MMA, a rare inherited disorder, is the most common organic aciduria in Mainland China [11, 12]. MMAs encompass a group of genetically heterogeneous autosomal recessive disorders stemming from defective metabolic pathways involving MMUT or its cofactor, cobalamin [13]. The clinical manifestation of MMA is intricate, ranging from asymptomatic disease to severe multisystem injuries and even death. MMAs tend to occur at any age, from prenatal to adult life [14, 15]. From June 1998 to December 2020, our hospital diagnosed 1,266 cases of MMA in Mainland China [11, 16, 17]. Predominant clinical presentations included psychomotor retardation and metabolic crisis [11, 18]. Multiorgan damage, including hematological abnormalities, pulmonary hypertension, kidney damage, eye disease, and skin lesion, was evident. Notably, megaloblastic anemia was a primary hematological abnormality [11, 16]. Cases 3 and 5 exhibited additional complexities, including liver function abnormalities and precocious puberty. Unfortunately, dual diagnoses were identified in these cases through whole-exome sequencing, underscoring the necessity for detailed history and physical examination in clinical practice.

It is conceivable that clinical signs and symptoms of multiple appropriately characterized disorders may exhibit similar biochemical and radiological attributes. This can lead to the masking and/or overlooking of one disorder if another affecting a similar system is present. Even if an atypical feature or pattern is identified, it is often attributed to the primary diagnosis, with secondary diagnoses potentially being overlooked. Consequently, the atypical feature of one disease may inaccurately reflect another undiagnosed condition, emphasizing the need for careful consideration of the complete assessment.

In cases where the clinical picture is atypical or exhibits more severity than expected, the possibility of a dual diagnosis (“double trouble”) should be contemplated [3]. Recent cases highlight the ongoing necessity for meticulous clinical evaluation, including a thorough physical examination, particularly in patients with atypical clinical features. The identification of another condition can significantly influence genetic management and counseling [2, 3].