Alström syndrome in a Chinese girl: a case report and literature review

Introduction

Alström syndrome (ALMS) (OMIM #203800) was first described in 1959 by a Swedish physician Alström, with subsequent patients reported sporadically. The current estimated prevalence is less than 1:1,000,000, making it a rare autosomal recessive disorder (1). To date, nearly 2,000 cases of ALMS have been reported globally, and over 600 pathogenic variants have been identified.

ALMS is also known as the obesity-retinal degeneration-diabetes syndrome. The causative gene, ALMS1, is located on the short arm of chromosome 2 (2p13) and encodes the ALMS1 protein. While the precise function of this protein remains unclear (2), it is currently believed to be involved in various intracellular signaling pathways and biological processes, particularly those related to ciliary function (3). Dysfunction of the ALMS1 protein leads to ciliopathy, which affects the cilia of retinal pigment epithelial cells, resulting in retinal degeneration and subsequent visual impairment. This manifestation is a characteristic feature of ALMS. Other classic clinical presentations include nystagmus, childhood obesity, infantile cardiomyopathy, diabetes mellitus, sensorineural hearing loss, and renal dysfunction (4).

We report the case of a girl from Shandong, China, who presented with complex clinical manifestations. Genetic testing revealed mutations in the ALMS1 gene, leading to a definitive diagnosis of ALMS. We also review the recent literature concerning the molecular genetics, clinical diagnosis, and management of this disorder. It summarizes recent global literature reports on ALMS and compares the clinical manifestations of various cases. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0217/rc).

Case presentation

A 14-year-old female was admitted with the gynecology department due to persistent abdominal pain. Gynecological ultrasonography suggested ovarian pedicle torsion, and she underwent emergency laparoscopic ovarian cystectomy. Upon admission, laboratory tests revealed a fasting blood glucose of 14.5 mmol/L (reference range: 3.9–6.1 mmol/L), a glycated hemoglobin (HbA1c) of 12.4%, and a blood ketone level of 16.0 mg/dL. Postoperatively, she was transferred to the endocrinology department for further management of diabetic ketoacidosis. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s legal guardians for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Past history: nystagmus was noted at the age of 1 year. During early childhood, she exhibited significant photophobia and blinking in bright light, accompanied by blurred vision; however, night vision was relatively preserved. Over the past 3–4 years, her visual acuity further deteriorated, with only light perception during the day but relatively maintained night vision. Hearing was normally reported, although she experienced recurrent otitis media during colds, which resolved with treatment. At age 8, learning difficulties were observed, characterized by good memory but poor arithmetic skills. For more than 6 months, she had experienced polydipsia, polyuria, and polyphagia, without significant weight loss. Family and personal history: both parents are healthy. Her father was 168 cm tall, and her mother was 156 cm tall. The patient was born vaginally at 36 weeks gestation. At around 8 months old, frequent blinking, photophobia, and facial asymmetry were noted. Bilateral breast development began between the ages of 11 and 12 years. Menarche was at age 13, with menstrual cycles lasting 3–6 days and occurring every 15–30 days.

Physical examination: height was 148 cm [−1.86 standard deviation (SD)], weight was 47 kg, body mass index (BMI) was 21.46 kg/m², arm span was 145 cm, upper segment was 69 cm, lower segment was 79 cm, sitting height was 82 cm, head circumference was 53 cm, chest circumference was 82 cm, waist circumference was 74 cm, abdominal circumference was 76 cm, and hip circumference was 93 cm. She was a well-appearing adolescent female with short stature Figure 1A. Acanthosis nigricans was present on the neck and axillae. Examination revealed curved little fingers Figure 1B, slightly short fourth metacarpals, and short fourth toes Figure 1C. The chest was unremarkable. Breast development was Tanner stage III. Pubic hair was present (Tanner stage II), but axillary hair was absent.

Figure 1 Patient’s physical characteristics. (A) General appearance; (B) curved little fingers; (C) short fourth toes. This image is published with the patient/participant’s consent.

The patient was born on October 21, 2009, at 36 weeks of gestation. On November 10, 2023, she presented to the gynecology department of our hospital with persistent abdominal pain. Following surgery, she was transferred to our department on November 12, 2023, where further investigations were conducted. Genetic testing performed on November 16, 2023, confirmed the diagnosis. The patient subsequently visited our department again on January 2, 2024, for better glycemic management. A telephone follow-up was completed on October 5, 2025.

Complete blood count with differential revealed a white blood cell count of 6.52×10⁹/L (reference range: 4.1–11×10⁹/L), red blood cell count 3.96×10¹²/L (4.1–5.3×10¹²/L), hemoglobin 109 g/L (114–154 g/L), platelet count 253×10⁹/L (150–407×10⁹/L), neutrophil count 3.32×10⁹/L (1.8–8.3×10⁹/L). Lipid profile testing showed triglycerides of 7.29 mmol/L (0–1.7 mmol/L), total cholesterol 6.12 mmol/L (0–5.18 mmol/L), high-density lipoprotein cholesterol 1.06 mmol/L (1.29–1.55 mmol/L), low-density lipoprotein cholesterol 3.62 mmol/L (0–3.36 mmol/L). Thyroid, renal, and liver function tests, cardiac enzymes, and coagulation parameters, including D-dimer, were all within normal limits. Sex hormone analysis showed a testosterone level of 0.38 ng/mL (reference range: 0.084–0.35 ng/mL), whereas all other parameters were within normal limits. No abnormalities were detected in cortisol rhythm, ACTH rhythm, or urinary free cortisol levels. The results of the steamed bun meal C-peptide release test are presented in Table 1. Body composition analysis results are presented in Table 2.

Diabetes complication screening, urine protein testing revealed a urinary microalbumin level of 995.0 mg/L and urinary microalbumin excretion rate of 912.1 µg/min. Fundus examination revealed waxy yellow optic discs bilaterally, attenuated retinal vessels, and retinal pallor with bone spicule-like pigment deposits. The ophthalmologic impression included bilateral nystagmus, bilateral strabismus, bilateral hemeralopia, and possible cone dystrophy. Electrocardiography (ECG) revealed sinus tachycardia and mild ST-T segment changes. Bilateral hand and foot radiographs demonstrated slightly shortened fourth metacarpals and bilaterally shortened fourth metatarsals, which were considered likely developmental abnormalities (Figure 2). Thyroid ultrasonography revealed a cystic nodule in the right thyroid lobe (C-TIRADS 2), a cystic-solid nodule in the left thyroid lobe (C-TIRADS 3), and heterogeneous thyroid parenchyma. Abdominal ultrasound: hepatomegaly and splenomegaly; otolaryngology evaluation, video otoscopy: bilateral patent external auditory canals, left tympanic membrane intact but cloudy, right tympanic membrane erythematous with yellowish tint and possible middle ear effusion. Tympanometry: type B curves bilaterally. Pure-tone audiometry demonstrated air conduction thresholds of 71 dB in the right ear and 53 dB in the left ear, with bone conduction thresholds of 40 dB and 28 dB, respectively. Neuropsychological assessment, Wechsler intelligence test: (I) verbal score: <40; (II) performance score: <40, full-scale intelligence quotient (IQ): <40; (III) social adaptive functioning: moderate impairment (7 points). Genetic testing: based on the patient’s complex and varied clinical manifestations, ALMS was suspected. To confirm this possibility, whole-exome sequencing was performed on the patient and her parents. The results revealed compound heterozygous pathogenic variants in the ALMS1 gene in the child. One pathogenic variant, c.6436C>T, was inherited from the mother and had been previously reported in the literature Figure 3A. The other variant, c.4839dupA, was a novel mutation inherited from the father Figure 3B. Considering the clinical manifestations, laboratory findings, and the compound heterozygous variants in the ALMS1 gene, the patient was definitively diagnosed with ALMS. A pedigree chart was constructed based on the family history and genetic testing results Figure 4.

Figure 2 X-ray. (A) Slightly short fourth metacarpals; (B) bilateral shortened fourth metatarsals.

Figure 3 The whole-exon sequencing of the child. (A) One variant site (arrow) c.6436C>T from her mother. (B) The other variant site (arrow) c.4839dupA from her father. Het., heterozygous mutation.

Figure 4 Pedigree chart. The arrow indicates the proband. Circles represent females, squares represent males. Fully shaded shapes represent affected individuals, half-shaded shapes represent phenotypically normal carriers, and gray shapes represent individuals who have not undergone genetic testing.

The patient was ultimately diagnosed with ALMS, diabetes mellitus, diabetic nephropathy, ovarian cyst with torsion (postoperative status), thyroid nodules, hepatomegaly, splenomegaly, chronic kidney disease, secretory otitis media, and mixed hearing loss. Treatment involved lifestyle interventions, including dietary management and increased physical activity. Pharmacological therapy was initiated with metformin hydrochloride tablets (0.5 g three times daily and 0.25 g at bedtime) for glycemic control, and Shenfukang (1.2 g three times daily) for renal protection. During hospitalization, the patient’s blood glucose levels were relatively well controlled. A telephone follow-up was conducted on October 15, 2025. At that time, the patient was 16 years old. According to her mother, her current height is 152 cm, and her blood glucose control is poor. The patient expressed satisfaction with the treatment process and indicated a willingness to undergo a follow-up evaluation in the near future; however, she has not yet returned to the hospital for a visit.

Discussion

ALMS (MIM #203800) was a rare autosomal recessive disorder. Although ALMS1 is currently the only confirmed disease-causing gene, there is considerable variability in clinical features, age of onset, and disease severity among individuals carrying identical mutations.

We will discuss the clinical heterogeneity of ALMS through a case carrying a novel ALMS1 mutation, and emphasize the importance of early recognition and multidisciplinary management.

Firstly, A study by Geberhiwot et al. (5) indicates that ALMS1 localizes to non-centrosomal sites, including adipocytes, supporting its involvement in vesicle trafficking and insulin signaling, which accounts for the diverse and highly heterogeneous clinical manifestations. Due to a reduction in hematopoietic stem/progenitor cells (HSPCs) accompanied by extensive fibrosis, the disease accelerates patient aging (6), leading to progressively worsening clinical features with age. Adults often develop blindness, restrictive cardiomyopathy, chronic kidney disease, intellectual impairment, and gastrointestinal dysfunction. Visual impairment is typically the initial symptom in neonates and tends to deteriorate rapidly (7). The majority of affected individuals meet the criteria for legal blindness after the age of 8. Visual impairment is often the most severe feature. Consequently, ocular manifestations commonly serve as the initial prominent symptom of ALMS (8) and represent the primary reason for seeking medical attention.

Hearing loss is the second most common manifestation and can be detected as early as 1 year of age, with 70% of cases diagnosed by 10 years old. The pathogenesis is thought to involve postnatal alterations in cochlear outer hair cells, with hearing loss progressing at a rate of approximately 10–15 dB per decade (9). There is also a significant risk of cardiovascular disease, primarily manifested as dilated cardiomyopathy. This association is suggested by a study involving five Chinese children (10), which indicates a potential link to ALMS1 protein dysfunction. Early detection is possible using ECG and natriuretic peptide levels; ECG abnormalities, such as nonspecific ST-segment changes and poor R-wave progression, are found in 40% of patients (11). Additionally, a cardiomyocyte model derived from gene-edited induced pluripotent stem cells (12) reflects the accelerated cardiac aging process. In this patient, the parents first noticed nystagmus but did not take it seriously. As the disease progressed, the patient presented due to ovarian torsion. The clinical manifestations after presentation were essentially consistent with those reported in the above-mentioned studies on ALMS. Furthermore, findings from a survey by Wanninayake et al. (13) indicate that limb deformities observed in some children may also represent a characteristic feature of the diverse clinical spectrum of ALMS. The patient’s deformities primarily consisted of bilateral shortening of the 4^th metacarpal and metatarsal, whereas most articles did not emphasize the description of deformities in patients.

Additionally, up to 50% of patients exhibit growth hormone (GH) deficiency, and short stature may be associated with damage to the insulin-like growth factor-1 (IGF-1) axis or pituitary fibrosis (14). Developmental milestones may be delayed, and a minority of patients have cognitive impairment (IQ <70). Some patients are susceptible to fibrotic changes in the ovaries or testes (15) with a high incidence of ovarian cysts that can affect fertility.

ALMS is a monogenic disorder caused by homozygous or compound heterozygous variants in the ALMS1 gene located on chromosome 2p13. These variants include splice-site mutations, deletions, insertions (16), and translocations (17); they cluster in exons 8 (6.1 kb), 10 (1.9 kb), and 16 (1.2 kb), which are considered mutation hotspots (18). Based on the clinical presentation and history, ALMS was highly suspected in this patient. Whole-exome sequencing revealed compound heterozygous variants in the ALMS1 gene: NM_015120.4: c.6436C>T(p.Arg2146*), NM_015120.4: c.4839dupA(p.Gly1614Argfs*27), consistent with the genetic profile of ALMS. The c.4839dupA variant is a novel pathogenic mutation not listed in the ClinVar or gnomAD databases. In contrast, the c.6436C>T variant is documented in these databases and has been previously reported in the literature.

There is currently no effective cure for this disease. Management focuses on delaying disease progression and providing symptomatic treatment to improve the patient’s quality of life and long-term prognosis (19). Additionally, a study by Dauleh et al. (20) demonstrated that the use of glucagon-like peptide-1 (GLP-1) receptor agonists can significantly improve metabolic parameters in patients with ALMS, suggesting that some individuals may benefit from treatment with semaglutide. Therefore, optimal disease management for ALMS requires a multidisciplinary team (MDT) based in an expert center, working in close liaison with community care providers for early identification and intervention. Furthermore, research by Ferch et al. (21) highlights the potential of effectiveness of the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1-agonist tirzepatide as a novel therapeutic option, which may improve glycemic control, ameliorate fatty liver disease, and effectively reduce body weight in affected patients. These findings demonstrate that therapeutic strategies for ALMS continue to advance.

Additionally, Bea-Mascato and Valverde (22) identified significant genetic and phenotypic heterogeneity, which precludes the establishment of a clear genotype-phenotype correlation map. Given the weak correlation between the location of ALMS1 gene variants and the resulting phenotypes, we conducted a comprehensive review of the literature to analyze the variability in clinical manifestations of ALMS. Through a literature search encompassing the following terms: Alström syndrome, ALMS1 gene, and the last 5 years, we reviewed the references of included studies and other relevant literature to identify additional related research. Studies were included if they fully provided clinical characteristics and genetic test reports. Our search identified nine cases of this disease, in addition to our own case. Data on age, gender, and disease manifestations were extracted from the case reports. The results are presented in Table 3. Based on the review of recent literature reports on patients with ALMS, it has been observed that these cases highlight the increasing genotypic diversity and clinical complexity of the syndrome. Most patients with different genotypes commonly present with visual and auditory impairments as well as impaired liver function, while other clinical manifestations vary among individuals.

In summary, we reported a patient with ALMS carrying a novel ALMS1 variant, c.4839dupA (p.Gly1614Argfs*27), which expands the known mutational spectrum of ALMS1. This case highlights the marked clinical heterogeneity of ALMS and emphasizes the importance of considering this diagnosis in children and adolescents presenting with diabetes, visual impairment, and multisystem involvement. Early genetic diagnosis and multidisciplinary management may improve long-term outcomes and quality of life.

The main limitation of this study is that it reports only a single confirmed case, representing a relatively small sample size, and the patient had not attended recent follow-up visits for comprehensive relevant investigations. The strength of this report lies in the identification of a novel genotype, supported by comprehensive ancillary investigations and the distinct clinical features of the patient. By the time we concluded the case, the patient was able to care for herself, although her blood glucose levels remain unstable. She was satisfied with the medical care received and was willing to return for regular follow-up.

Acknowledgments

The authors would like to thank the patient and her families at first, as this work would not have been possible without their participation.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0217/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0217/prf

Funding: This study was supported by the Shandong Province Medical and Health Science Technology Project of Shandong Province (No. 202403060200).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2026-0217/coif). The authors have no conflicts of interest to declare.

Ethical Statement: 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 this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient’s legal guardians for the publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Zhang Q, Ding Y, Feng B, et al. Molecular and Phenotypic Expansion of Alström Syndrome in Chinese Patients. Front Genet 2022;13:808919. [Crossref] [PubMed]
2. Bea-Mascato B, Gómez-Castañeda E, Sánchez-Corrales YE, et al. Loss of the centrosomal protein ALMS1 alters lipid metabolism and the regulation of extracellular matrix-related processes. Biol Direct 2023;18:84. [Crossref] [PubMed]
3. Choudhury AR, Munonye I, Sanu KP, et al. A review of Alström syndrome: a rare monogenic ciliopathy. Intractable Rare Dis Res 2021;10:257-62. [Crossref] [PubMed]
4. Tahani N, Maffei P, Dollfus H, et al. Consensus clinical management guidelines for Alström syndrome. Orphanet J Rare Dis 2020;15:253. [Crossref] [PubMed]
5. Geberhiwot T, Baig S, Obringer C, et al. Relative Adipose Tissue Failure in Alström Syndrome Drives Obesity-Induced Insulin Resistance. Diabetes 2021;70:364-76. [Crossref] [PubMed]
6. Dassie F, Albiero M, Bettini S, et al. Hematopoietic Stem Cells and Metabolic Deterioration in Alström Syndrome, a Rare Genetic Model of the Metabolic Syndrome. Endocrinology 2023;164:bqad011. [Crossref] [PubMed]
7. Wang Y, Huang L, Sun L, et al. Ocular findings and genetic test in Alström syndrome in childhood. Exp Eye Res 2022;225:109277. [Crossref] [PubMed]
8. Sinha A, Leeson-Beevers K, Lewis C, et al. Alström syndrome: the journey to diagnosis. Orphanet J Rare Dis 2025;20:5. [Crossref] [PubMed]
9. Lindsey S, Brewer C, Stakhovskaya O, et al. Auditory and otologic profile of Alström syndrome: Comprehensive single center data on 38 patients. Am J Med Genet A 2017;173:2210-8. [Crossref] [PubMed]
10. Qi Y, Lu J, Sun N, et al. Alström syndrome: A rare cause of dilated cardiomyopathy in five Chinese children. Gene 2025;944:149285. [Crossref] [PubMed]
11. Brofferio A, Sachdev V, Hannoush H, et al. Characteristics of cardiomyopathy in Alström syndrome: Prospective single-center data on 38 patients. Mol Genet Metab 2017;121:336-43. [Crossref] [PubMed]
12. Patel L, Roy A, Barlow J, et al. Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model. Mol Genet Metab 2024;143:108575. [Crossref] [PubMed]
13. Wanninayake S, Paisey R, Dabasia H, et al. Musculoskeletal deformities of Alström syndrome-a review of 55 cases. Orphanet J Rare Dis 2025;20:367. [Crossref] [PubMed]
14. Han JC, Reyes-Capo DP, Liu CY, et al. Comprehensive Endocrine-Metabolic Evaluation of Patients With Alström Syndrome Compared With BMI-Matched Controls. J Clin Endocrinol Metab 2018;103:2707-19. [Crossref] [PubMed]
15. Marshall JD, Bronson RT, Collin GB, et al. New Alström syndrome phenotypes based on the evaluation of 182 cases. Arch Intern Med 2005;165:675-83. [Crossref] [PubMed]
16. Taşkesen M, Collin GB, Evsikov AV, et al. Novel Alu retrotransposon insertion leading to Alström syndrome. Hum Genet 2012;131:407-13. [Crossref] [PubMed]
17. Hearn T, Renforth GL, Spalluto C, et al. Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. Nat Genet 2002;31:79-83. [Crossref] [PubMed]
18. Marshall JD, Muller J, Collin GB, et al. Alström Syndrome: Mutation Spectrum of ALMS1. Hum Mutat 2015;36:660-8. [Crossref] [PubMed]
19. Peng H, Li K, Xue B, et al. Endocrine metabolism characteristics of Alström syndrome in 25 Chinese patients and identification of a new splice site in the ALMS1 gene. Diabetol Metab Syndr 2025;17:383. [Crossref] [PubMed]
20. Dauleh H, Mohammed I, Hussain K. Efficacy of Semaglutide in Pediatric Patients With Bardet-Biedl Syndrome and Alström Syndrome. JCEM Case Rep 2025;3:luaf266. [Crossref] [PubMed]
21. Ferch M, Peitsch I, Kautzky-Willer A, et al. Effectiveness of the Dual GIP/GLP1-Agonist Tirzepatide in 2 Cases of Alström Syndrome, a Rare Obesity Syndrome. J Clin Endocrinol Metab 2025;110:3364-9. [Crossref] [PubMed]
22. Bea-Mascato B, Valverde D. Genotype-phenotype associations in Alström syndrome: a systematic review and meta-analysis. J Med Genet 2023;61:18-26. [Crossref] [PubMed]
23. Zhang MT, Gao MY, Wang SJ. Analysis of clinical manifestations and genetic characteristics of a case of Alstrom syndrome. Shandong Medical Journal 2024;64:57-60.
24. Chen HF, Zuo WT, Zhao LZ, et al. A case of Alstrom syndrome caused by compound heterozygous variation of ALMS1. Journal of International Reproductive Health/Family Planning 2025;44:459-63.
25. Ma MX, Zhang JG, Zhou SX. Alstrom syndrome: a case report and literature review. Chinese Pediatrics of Integrated Traditional and Western Medicine 2024;16:38-41.
26. Xu PC, Li XB, Zhuang XH, et al. Alstrom syndrome in children: a report of two cases and literature review. Journal of Shandong University (Health Sciences) 2024;62:107-11.
27. Yen B, Ciftci MD, Afrashi F, et al. A Case Of Alström Syndrome With A Novel Variant In Alms1 Gene Presenting With Cone Rod Dystrophy As First Finding. Retin Cases Brief Rep 2025;19:413-7. [Crossref] [PubMed]
28. Shinkawa K, Ishii A, Kimura T, et al. A Case of Siblings with End-Stage Kidney Disease and Retinal Degeneration Suggestive of Partial Alström Syndrome. Nephron 2025; Epub ahead of print. [Crossref]
29. Herranz-Heras JC, Barceló A, Quesada-Espinosa JF, et al. Alström syndrome: Two clinical cases with two novel pathogenic variants. Eur J Ophthalmol 2023;33:NP27-31.