Infant Alstrom syndrome diagnosed by a new gene mutation: a case report

Abstract

Alstrom syndrome is a rare autosomal recessive disorder resulting from an ALMS1 gene mutation. Here, we present the clinical data of a case of an infant diagnosed with Alstrom syndrome through whole-exome sequencing. A 2-month-old male infant was admitted to Sichuan Provincial Maternity and Child Health Care Hospital on 30 May 2019 after “coughing for half a day and dyspnea for 2 hours”. He was diagnosed with severe pneumonia, acute congestive heart failure, Grade III cardiac function, acute respiratory failure, and myocarditis. After treatment, he was discharged with a prescription for oral medication. After a 4-month follow-up, the patient’s left ventricle exhibited spherical enlargement and a decrease in left ventricular function. The infant’s whole-exome sequencing results revealed compound heterozygous mutations in the ALMS1 gene: c.2179dup (p. Y727Lfs*12), a frameshift mutation, that was heterozygous and originated from the mother, while c.11140C>T (p. Q3714*) was a heterozygous nonsense mutation that originated from the father. Both mutations are classified as “category 1-pathogenic mutations” according to the American College of Medical Genetics and Genomics (ACMG) assessment. A novel ALMS1 mutation was identified in this case report, highlighting the importance of genetic testing for the early diagnosis of Alstrom syndrome.

Introduction

Alstrom syndrome (ALMS) is a rare autosomal recessive disorder that was first reported in 1959. It is characterized by obesity, retinal degeneration, progressive sensorineural deafness, cardiomyopathy, and insulin resistance (IR), as well as other multi-organ involvements. ¹ The incidence of ALMS is estimated to be 1 to 9 in 1 million, with approximately 1050 cases reported globally at present (Human Gene Mutation Database, HGMD, http://www.hgmd.cf.ac.uk/ac/search.php). ² The clinical manifestations of the disease exhibit age-related variability, and the progressive multi-organ dysfunction may precipitate premature mortality in afflicted patients. However, this condition clinically presents with significantly heterogeneous features, onset time, and severity. Variations can even occur among family members who share the same genetic background. ³ Therefore, it is crucial to summarize the pathogenesis characteristics of diverse populations and conduct early genetic testing for suspected patients.

ALMS is a monogenic disorder that results from homozygous or compound heterozygous variants in the ALMS1 gene, which is located on chromosome 2p13. Approximately 270 pathogenic variants have been identified to date, of which 96% are nonsense or frameshift variants (insertions and deletions) that result in the production of truncated, nonfunctional proteins. ³

Here, we report a case of infantile-onset ALMS with cardiac dysfunction. The causative gene mutation locus was identified by whole-exome sequencing, which revealed an unreported novel mutation site at c.11140C>T (p. Q3714*).

Case report

A male patient, aged 2 months, was admitted to Sichuan Maternity and Child Health Care Hospital on 30 May 2019 because of a cough lasting half a day and shortness of breath for 2 hours. He was a gravida 3, para 3 (G3P3) infant born at full term with a birth weight of 3.5 kg. The perinatal period was uneventful and there was no significant historical background. The parents denied any family history or medical history that was similar. The parents did not have a consanguineous relationship. The admission physical examination stated the following: The patient’s temperature (T) was 36.6°C, with a pulse rate (P) of 162 beats per minute, respiratory rate (RR) of 60 breaths per minute, blood pressure (BP) of 81/55 mmHg, pulse oxygen saturation (SpO₂) of 90%, and body weight of 6.45 kg. He was conscious, but had poor mental responsiveness, a less rosy complexion, facial and eyelid swelling, and slight bluish discoloration around the lips. He exhibited dyspnea and displayed the visible inspiratory three-concave sign during inspiration. The heart sounds were low and dull, with a regular rhythm. The breath sounds in both lungs were symmetrical and audible, accompanied by a few medium-thick wet rales and wheezing. The liver was palpable at 3.5 cm below the costal margin, exhibiting a medium texture and blunt margins. Bilateral lower extremity edema was present. The capillary refill time (CRT) was 3 s.

Auxiliary examinations included the following: No abnormalities were detected in the blood routine, C-reactive protein (CRP), liver function, renal function, or myocardial enzyme spectrum. The cardiac troponin T (cTnT) level was 0.511 ng/mL, while the brain natriuretic peptide (BNP) level was found to be elevated at 4059 pg/mL. Echocardiography (ECG) revealed a significant reduction in left ventricular systolic function, with an ejection fraction (EF) of 34% and fractional shortening (FS) of 15%. Left atrial (LA) enlargement was noted, with an internal diameter of 17 mm. The left ventricle (LV) showed slight enlargement, with an internal diameter of 27 mm, and abnormal wall motion. Moderate mitral valve regurgitation was detected. The chest CT scan revealed bilateral pneumonia and cardiomegaly. The electrocardiogram revealed sinus rhythm, T-wave alterations, and reduced voltage in the limb leads (Figure 1). Combined with the clinical manifestations and auxiliary examinations, a diagnosis of severe pneumonia, acute congestive heart failure (CHF), cardiac function class III, acute respiratory failure, and myocarditis was considered.

Figure 1.

The 12-lead electrocardiogram.

We obtained parental consent for all treatments. Endotracheal intubation and mechanical ventilation were promptly initiated upon hospitalization, with the latter being discontinued on 6 June 2019. Cefdone sodium and sulbactam sodium (50 mg/kg, intravenously guttae, every 8 hours for 14 days) were administered for anti-infective therapy, and intravenous infusion of gamma globulin (1 g/kg, intravenously guttae, every day for 2 days) was given to enhance immune function. Methylprednisolone (1 mg/kg, intravenously guttae, every 12 hours for 4 days) was administered for anti-inflammatory effects, followed by sequential prednisone therapy (10 mg per os (PO) once daily in the morning for 2 days, then reduced to 5 mg PO once daily for an additional 5 days). Digoxin (30 mL:1.5 mg specification) was given orally every 12 hours for a total of 15 days and discontinued when the heart rate fell below 90 beats per minute. Dopamine infusion at a dose of 5 μg/kg/minute was used intravenously for 1 day to enhance cardiac function. Creatine phosphate sodium was administered to nourish the myocardium, while furosemide was given for diuresis. Other treatments were also given to the patient. The patient exhibited good tolerance to all treatments administered during hospitalization.

The child’s condition showed improvement on 21 June 21 2019, and he was subsequently discharged from the hospital. Although there was an improvement in cardiac function at the time of discharge, it did not fully recover to normal levels (EF of 45%). He received treatment with oral low-dose prednisone (5 mg PO once daily), spironolactone (2 mg/kg PO every 12 hours), digoxin (0.3 mL PO every 12 hours), and captopril (0.5 mg/kg PO every 12 hours). It was advised for the patient to visit an outpatient clinic weekly for ECG review and medication adjustment as necessary. The compliance and tolerance were satisfactory upon evaluation by the cardiologist following discharge. However, the child’s cardiac function gradually deteriorated during the follow-up period. A repeat ECG was performed after a 4-month interval (Figure 2a–2b), revealing significant left ventricular enlargement and sphericity (LV diameter of 37 mm), convexity of the ventricular septum towards the right ventricle, flatted left ventricular motion, decreased left ventricular function (EF of 33%, FS of 15%), and moderate mitral regurgitation.

Figure 2.

The echocardiography (ECG) performed 4 months after discharge. (a) M-mode ECG showed that the left ventricle was significantly enlarged and spherical (left ventricle (LV): 37 mm), and the left ventricular function was decreased (ejection fraction (EF): 33%, fractional shortening (FS): 15%). (b) Two-dimensional ECG detected that the ventricular septum was convex to the right ventricle, the left ventricular motion was flat, and there was a moderate mitral regurgitation.

After obtaining informed consent, 3 mL of peripheral blood was collected from the patient and his parents for high-precision clinical exome sequencing. Sequencing was conducted using the capture library construction approach with a Novaseq 6000 high-throughput sequencing depth of 200×. The hg19 genome served as the reference for comparative analysis. Sanger sequencing validated the variant sites and elucidated the source of the variant. Variants were evaluated for their pathogenicity based on the guidelines set forth by the American College of Medical Genetics and Genomics (ACMG) . The complete genetic testing revealed a compound heterozygous mutation in the ALMS1 gene of this child (Figure 3a–3b): c.2179dup (p. Y727Lfs*12) (exon 8), which is a heterozygous frameshift mutation; and c.11140C>T (p. Q3714*) (exon 16), which is a heterozygous nonsense mutation. According to the ACMG assessment, both variants have been classified as “category 1-pathogenic variants”. The child inherited the c.11140C>T variant of the ALMS1 gene from his father and the c.2179dup variant from his mother. Through both copy number and single nucleotide polymorphism (SNP) analysis, no copy number variation (CNV) was identified that could be linked to the clinical manifestations. In conclusion, the patient was diagnosed with ALMS based on the primary diagnostic criteria. To assess the patient’s hearing ability, the auditory brainstem response and otoacoustic emission examinations were conducted, which revealed no apparent abnormalities. The patient did not show any overt indications of visual impairment, nor nystagmus or photophobia, but the parents declined a fundus examination. He did not present with obesity from birth until 7 months of age, and his blood glucose was within normal range during hospitalization. Despite our efforts to follow up with the patient, we were unable to do so after obtaining clear results from full exon sequencing.

Figure 3.

Confirmation of two mutations in the ALMS1 gene in the family members by Sanger sequencing. (a) c.11140C>T (p. Q3714*) mutation from the patient’s mother. (b) c.2179dup (p. Y727Lfs*12) mutation from the patient’s father. Het., heterozygous mutation.

We present this case in compliance with the CARE reporting checklist. ⁴ The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). As the patient was an infant, parental verbal informed consent was obtained for the publication of this case report and accompanying images.

Discussion

ALMS is an exceedingly uncommon multisystem hereditary disease, and its symptoms and signs exhibit significant heterogeneity across individuals and age groups. The current clinical diagnostic criteria for ALMS consist of primary and secondary criteria. The primary criteria pertain to the identification of a pathogenic mutation in one allele of ALMS1, or a family history of ALMS and vision impairment. Secondary criteria comprise obesity, insulin resistance or type 2 diabetes, dilated cardiomyopathy by congestive heart failure, and hearing impairment. ⁵ Some symptoms, such as nystagmus and photophobia, manifest at birth, while others, like high blood pressure and kidney failure, emerge during the child's growth. The case reported here occurred during infancy and primarily manifested with cardiac enlargement and decreased cardiac function. Early diagnosis based on clinical presentations is exceedingly challenging because of the lack of apparent manifestations other than those already observed. This case serves as a reminder that genetic testing should be considered in cases where clinical diagnosis is ambiguous or therapeutic outcomes are unexpectedly poor. ⁶

ALMS results from mutations in the ALMS1 gene, which is situated on chromosome 2p13. The ALMS1 gene spans a total length of 224 kb, comprising 23 exons, and encodes a protein product consisting of 4169 amino acids (nM_015120.2). ⁷ ALMS1 is widely expressed and localizes to the centrosome and basal body of tissue ciliated cells, including the central nervous system, photoreceptors, cardiopulmonary, reproductive, endocrine, and urinary systems. ⁸ Although its exact biological function remains unclear, current evidence suggests that it plays a role in maintaining ciliary function, intracellular transport, and adipocyte differentiation.^8,9

To date, more than 300 mutations of the ALMS1 gene have been documented, encompassing point mutations, deletions, insertions, and frameshifts (HGMD), most of which are nonsense mutations, small deletions, or insertions. According to ALMS1 gene database statistics, most mutations occur in exons 8, 10, and 16, with a few reported mutations located in exons 9, 11, 12, 15, 18, and intron 17. Notably, these mutations are predominantly found within exon 16. Mutations within this gene were responsible for 36% of cases. ⁵ The patient’s ALMS1 gene in this case exhibited both a c.2179dup (p. Y727Lfs*12) frameshift mutation and a c.11140C>T (p. Q3714*) nonsense mutation. The former mutation, located in exon 8, was previously reported to result in retinal degeneration and obesity across all patients, albeit with some experiencing delayed onset of visual impairment (1 to 5 years). ¹ The newly identified variant c.11140C>T (p. Q3714*) is a nonsense mutation located in exon 16. Gene sequence analysis revealed that this variant results in the substitution of C by T at position 11,140 within the coding region of the gene, leading to the conversion of codon 3714 into a stop codon. This premature termination of protein translation causes a truncated protein consisting of only 3713 amino acids, ultimately resulting in disease. These two variants are classified as “category 1-pathogenic variants” according to the ACMG Variant Classification Guidelines. ¹⁰ The mutation c.10775delc in exon 16 is the predominant type of ALMS1 gene mutation, accounting for 50% of cases in the UK. ⁸ In this case, the novel c.11140C>T (p. Q3714*) mutation in exon 16 is reported for the first time across diverse ethnic groups both domestically and internationally. Some scholars have noted that mutations located in exons 16 and 8 exhibit more intricate clinical phenotypes and more severe disease, ⁸ presenting as multiple organ lesions, including in the heart, eyes, ears, liver, and kidneys.

Abnormal lipid metabolism resulted in dilated cardiomyopathy congestive heart failure as the initial symptoms in this patient. Because of the early onset, no other clinical manifestations were observed. Previous reports indicated that ALMS patients predominately succumb to heart failure during childhood (about 90.5%), while in adulthood, they are more likely to die from either heart or kidney failure (61.3%). ¹¹ About 40% of ALMS infants experience mortality during the period between three and 4 weeks of age. ¹¹ Failure to conduct routine genetic testing in cases of severe cardiomyopathy at 6 months of age often results in premature death from underestimation of the condition. ³ ALMS cardiomyopathy can be classified into acute infantile cardiomyopathy and late-onset type based on the age of onset. Acute infantile cardiomyopathy typically presents within 3 months after birth, with a survival rate of 74% in children who received standard anti-heart failure treatment with reversible cardiac function and ventricular dilatation. However, approximately one-fifth of children may experience heart failure re-congestion. ³ Various types of cilia play a role in regulating cardiac development at different stages and locations. ¹² A deficiency of the ALMS1 protein can impede the development of primary cilia in cardiac cells, inhibit activation of Wnt/β-catenin signaling, suppress cell proliferation, and ultimately result in acute infantile mitotic cardiomyopathy.^13,14

The early diagnosis of ALMS typically relies on a phenotypic analysis and sequencing of the ALMS1 gene. However, because of the lack of simultaneous occurrence of the main symptoms, clinical manifestations alone are insufficient for early diagnosis of patients, particularly infants and young children.^8,9,15

For children diagnosed with cardiomyopathy, poor recovery of cardiac function, and other systemic damage, early alertness to ALMS and genetic testing should be performed. Here, we reported a rare case of infant ALMS. The mutation site in the ALMS1 gene further enriches the pathogenic variant database of this gene.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605231184100 - Supplemental material for Infant Alstrom syndrome diagnosed by a new gene mutation: a case report

Supplemental material, sj-pdf-1-imr-10.1177_03000605231184100 for Infant Alstrom syndrome diagnosed by a new gene mutation: a case report by Yujiao Ye, Xianmin Wang, Guixia Li, Xiao Xia Xuehong Ji in Journal of International Medical Research