TANGO2-related metabolic encephalopathy–arrhythmia syndrome unmasked in 22q11.2 deletion syndrome: hemizygous pathogenic variant, complex phenotype modified by two genetic conditions, and implications for proactive crisis prevention: a case report

Abstract

Background

TANGO2 deficiency disorder is an ultra-rare autosomal recessive condition characterized by life-threatening metabolic crises with rhabdomyolysis and cardiac arrhythmias.

Patients with 22q11.2 deletion syndrome are at increased risk when a pathogenic variant occurs in the remaining allele, yet this dual diagnosis remains underrecognized as clinicians often attribute all manifestations to the primary genetic condition.

We report a case of a child with confirmed 22q11.2 deletion syndrome in whom a coexisting variant in the TANGO2 gene was diagnosed at the age of 5 after first metabolic crisis with rhabdomyolysis.

Case presentation

A girl with 22q11.2 deletion syndrome diagnosed in infancy exhibited global developmental delay and chronic excessive sleepiness attributed to her established diagnosis. At age 5, she experienced her first metabolic crisis during pneumonia with severe rhabdomyolysis (creatine kinase >100,000 U/L), features inconsistent with isolated 22q11.2 deletion syndrome. Two additional metabolic crises occurred at age 7 before exome sequencing revealed a hemizygous TANGO2 variant c.536G>A, confirming TANGO2 deficiency. A previously unreported hemizygous missense variant c.536G>A (p.Gly138Glu) in the TANGO2 gene (NM_152906.7) was identified and verified by NGS-based deep amplicon sequencing and Sanger direct sequencing; segregation analysis confirmed paternal inheritance with the maternal allele deleted within the 22q11.2 region. Following diagnosis, B-vitamin supplementation, coenzyme Q10, L-carnitine, and gastrostomy tube placement were initiated to ensure consistent hydration and prevent prolonged periods without nutrition, a known crisis trigger. The patient achieved 4 years of crisis-free stability with reduced daytime sleepiness. At age 11, she remains stable without further crises.

Conclusions

This case demonstrates that exome sequencing should be pursued early when atypical features emerge in patients with established genetic diagnoses. The sustained crisis-free period following gastrostomy placement supports proactive nutritional intervention in TANGO2 patients with feeding difficulties. Clinicians must recognize that microdeletion syndrome patients can harbor variants unmasking additional autosomal recessive conditions requiring distinct management.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12887-026-07264-w.

Background

Microdeletion syndrome 22q11.2 (previously known as DiGeorge syndrome, OMIM:188400, ORPHA:567) is one of the most common microdeletion disorders [1, 2]. Differences in the length of the deleted fragment translate into differences in the clinical picture and severity of symptoms among patients, however metabolic crisis do not belong to the clinical picture of the disease [1–4].

Additional genomic variants in 22q11.2 deletion syndrome through variants in the second, unremoved allele can lead to manifestations of autosomal recessive diseases. To date, several syndromes caused by the hemizygous variants on the remaining allele in 22q11.2 region coexisting with 22q11.2 deletion syndrome have been described, including Bernard-Soulier syndrome type B (caused by variants in GP1BB; giant platelet cells, thrombocytopenia and prolonged bleeding time); CEDNIK syndrome (caused by variants in SNAP29; cerebral dysgenesis, neuropathy, ichthyosis and keratoderma, ); van den Ende-Gupta syndrome (caused by variants in SCARF2; severe contractile arachnodactyly and skeletal anomalies - VDEGS); Meier–Gorlin syndrome 7 (caused by variants in CDC45); Noonan syndrome 2 (caused by variants in LZTR1), potential variants of clinical significance in PI4KA and PRODH genes as well as recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration (MECRCN, caused by variants in TANGO2, transport and golgi organization 2 homolog) [2, 3]. The last of the mentioned, MECRCN, known as recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome or TANGO2 deficiency disorder as well as TANGO2-related metabolic encephalopathy and arrhythmias (OMIM:616878, ORPHA:480864) is an ultra-rare autosomal recessive disorder characterized by episodic encephalomyopathic crises [5–10].

The study describes a case of a child with confirmed 22q11.2 deletion syndrome in whom a coexisting variant in the TANGO2 gene was diagnosed at the age of 5.

Case presentation

We present a case of the girl with an uneventful family history, of non-consanguineous parents, born from the first pregnancy and delivery, at term, via caesarean section (due to tocophobia), with a birth weight of 2550 g, assessed with an Apgar score of 10 at both 1 and 5 min. A heart defect (septal defect between the atria and ventricles) was diagnosed after birth and child was underwent cardiac surgery. Due intraoperatively identified absence of the thymus, suspicion of 22q11.2 deletion syndrome was raised. MLPA molecular test revealed deletion of three markers for the critical region for 22q11.2 deletion syndrome. The diagnosis was confirmed by microarray CGH (deletion 2,6 Mb in region 22q11.2).

The child exhibited global developmental delay. She began to walk independently at the age of 3 years, with a markedly abnormal gait characterized by toe walking. She spoke her first single words at approximately 2 years of age; however, no significant progress in expressive language development was observed in the subsequent years. By the age of 5, she understood simple commands, spoke single words (about a dozen) and was learning alternative communication methods. Additionally, she was establishing emotional and social connections. The girl underwent ongoing rehabilitation, received lower limb orthoses, received speech therapy and educational support. Furthermore, since early childhood, the child’s mother observed episodes of excessive daytime sleepiness, weakness, and fatigue.

Until the age of 5 years, several sleep EEG recordings were obtained, initially normal and later showing mild generalized changes. Laryngological examinations revealed no evidence of cleft palate. Repeated blood tests did not reveal decreased calcium or ionized calcium levels.

At the age of 5, the girl was hospitalized due to worsening consciousness disorders and rhabdomyolysis in the course of pneumonia. Laboratory tests, besides elevated inflammatory parameters and acetonuria, showed, among others, extremely high creatine kinase activity (Table 1).

Table 1.

Selected laboratory parameters during acute metabolic crisis

Parameter	Level	Reference values
Creatine kinase	183,000 U/L	10–200 U/L
Aspartate aminotransferase	4166 U/L	0–40 U/L
Alanine aminotransferase	1894 U/L	0–41 U/L
Glycemia	37 mg/dl	70–99 mg/dl
Ammonia	155 umol/L	10–50 umol/L
Lactate	3,26 mmol/l	0,5 − 2,2 mmol/l

Intensive hydration with alkalinization, broad-spectrum antibiotics, were applied. After that gradual normalization of biochemical parameters was observed. The diagnostic process was expanded to include acylcarnitine profile using Tandem MS method (a significantly elevated C6 carnitine and slightly elevated C18:2OH carnitine were detected [see Additional file 1]) and organic acids profile in urine using GC/MS method (without significant deviations). After the incident, temporary developmental regression occurred, mainly in motor function, with gradual return to the pre-illness state within a few months.

Due to the metabolic crisis with accompanying rhabdomyolysis and the coexistence of 22q11.2 deletion syndrome, the presence of an additional pathogenic variant, such as in the TANGO2 gene, was suspected. Exome sequencing (ES) was performed using the Twist Human Core Exome+Twist mtDNA Panel+ Twist RefSeq panel (Biosence, San Francisco, CA, USA) according to manufacturer’s recommendations. Variant verification and the family study was performed by both NGS-based deep amplicon sequencing and Sanger direct sequencing. A hemizygous missense variant c.536G > A/ (p.Gly138Glu) was identified in the proband and in her father (carrier) in the TANGO2 gene (NM_152906.7, hg38: 22:020055975-G > A), while the other allele carries the deletion of a fragment of chromosome 22 encompassing the TANGO2 (hg38: 22:18906374–21209126) (Fig. 1), which was the basis for the diagnosis of MECRCN. In silico pathogenicity prediction of TANGO2: c.536G > A (p.Gly138Glu) was performed based on the in-house developed platform GeneBe [11] and American College of Medical Genetics and Genomics (ACMG) guidelines [12]. The p.Gly138Glu was classified as variant of uncertain significance (VUS); ACMG score: 3 points, PM2 Moderate. No other variant(s) revealed by ES corresponding to clinical phenotype or fulfilled frequency and pathogenicity criteria of gene variants were detected. The presence of hemizygous c.536G > A variant in the proband and heterozygous state in her father, was positively verified, while excluded in her mother, suggesting deletion of maternal allele.

Fig. 1.

Results of the family study of TANGO2 c.536G > A/(p.Gly138Glu) variant performed by NGS-based deep amplicon sequencing (Integrative Genomics Viewer snapshot is presented; left panel) and performed by Sanger sequencing (FinchTV snapshot is presented; right panel)

At the age of 7, the girl was hospitalized twice with symptoms of metabolic crisis (consciousness disorders, weakness, vomiting, metabolic acidosis, elevated creatine kinase levels - up to 30,925 U/L). Additionally, two, up to 10–15 s episodes including loss of contact and tonic muscle tension with subsequent post-ictal sleep without significant metabolic disorders in laboratory tests were observed. An outpatient electroencephalographic examination showed minor changes in the form of single, generalized spike-wave complexes.

Considering the observed feeding problems (slow eating, occasional choking on fluids), a decision was made to place a gastrostomy tube to ensure adequate hydration and caloric intake. Since then, the child has been less sleepy during the day.

At the age of 7.5, the girl was hospitalized for follow-up. Upon admission, she established normal visual contact, followed simple commands, and communicated mainly through gestures. Neurological examination revealed facial dysmorphic features (Fig. 2), alternating divergent strabismus, decreased muscle tone and strength, present tendon reflexes, higher in the lower limbs, discreetly marked Babinski reflex bilaterally, Achilles tendon contracture. Gait was mainly with support, cautious, slow, on flexed knees. Additional tests showed slightly decreased parathyroid hormone (12.77 pg/ml) and vitamin D (23.23 ng/ml) concentrations, with normal total calcium values. Creatine kinase, lactate, coenzyme Q10, free thyroxine, thyroid-stimulating hormone, and immunoglobulin concentrations were normal. The ECG recording showed regular sinus rhythm, right bundle branch block, with normal QTc interval (comparable to previous recordings). No evidence of cardiomyopathy was found on echocardiography.

Fig. 2.

Presented girl with 22q11.2 deletion syndrome and recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration at the age of 8

Flow cytometric immunophenotyping results showed decreased percentage of total T-cells and CD4 + T-cells, however their absolute count was within the reference range. Among the CD4 + compartment, CD4 + naive T-cells were decreased, while CD4 + terminally differentiated (TD) effector cells were elevated, both in percentage and absolute number. Within the CD8 + compartment, lower percentage of CD8+naïve cells and increased absolute number of CD8 + effector memory cells were observed (Table 2). White blood cell count (WBC) was within the normal range (8.56 G/L).

Table 2.

Flow cytometric immunophenotyping results

Parameter			Reference values (children 2–16 years)
	Percentage [%]	Absolute count [cells/ul]	Percentage [%] (range)	Absolute count [cells/ul] (range)
Total T-cells	16.4	1403.84	17.45–46.24	1296.75–4202.42
T-cells CD4+	7.8	667.68	8.91–27.96	663.02–2559.11
Naïve	3.0	256.8	5.15–21.36	316.37–2036.82
Effector Memory	0.8	68.48	0.15–1.45	10.55–96.21
Effector TD	0.62	53.07	0–0.49	0 – 43.85
T-cells CD8+	6.4	547.84	4.94–15.81	310.11–1384.49
Naïve	2.0	171.20	2.52–10.57	162.83–886.32
Effector Memory	1.2	102.72	0.02–1.53	1.62–78.83
Effector TD	0.44	37.66	0.05–6.43	3.02–533.66

Values beyond the reference ranges were marked in bold

In line with current knowledge regarding its potential beneficial effect on the course of MECRCN, supplementation of coenzyme Q preparation (45.5 mg/day), vitamin B complex (a supplement containing: vitamin B1-40 mg, vitamin B2-50 mg, vitamin B3-100 mg, vitamin B5-57 mg, vitamin B6- 1,4 mg, vitamin B7- 500 µg, folic acid − 200 µg, methyl folate − 200 µg, vitamin B12–100 µg) and L-carnitine was initiated (666.66 mg/day) [5, 10].

After discharge, episode resembling brief generalized tonic-clonic seizures were observed with no concurrent hypoglycaemia (including measurements directly during the incident) or electrolyte disturbances. Based on the overall clinical picture, epilepsy was diagnosed, and levetiracetam was initiated, achieving seizure control.

At the age of 8 years, a routine ophthalmologic examination raised suspicion of optic disc swelling, in the absence of clinical features of increased intracranial pressure. In the PVEP1 study P100 latencies were bilaterally normal, with amplitudes reduced to 75% in the right eye and 40% in the left eye. In the PVEP 15 study both latencies and amplitudes were normal. In magnetic resonance imaging of the head and orbits no abnormalities were found within the brain; however, bilaterally in the projection of the optic nerve heads, small, non-enhancing contrast-enhanced changes were observed, primarily corresponding to drusen.

As of the time of this publication, at the age of 11 years, the child remains in a stable cardiological condition and stable but retarded neurological status, without clinically expressed seizures, and no further episodes of metabolic crises have been recorded.

Discussion

Patient initially presented with a 22q11.2 deletion and 22q11.2 syndrome, accompanied by symptoms of metabolic decompensation and additionally, a variant of uncertain significance (VUS) in the TANGO2 gene was identified on the second allele. Given the clinical picture of metabolic decompensation, the complete deletion of the TANGO2 gene in the 22q11.2 region and the presence of a TANGO2 VUS variant on the other allele, a definitive diagnosis has been made for two conditions: 22q11.2 deletion syndrome and TANGO2-related disorder (Table 3).

Table 3.

Clinical characteristics of the presented patient with consideration of the overlay of two genetic disorders: 22q11.2 deletion syndrome and TANGO2-related metabolic encephalopathy and arrhythmias

22q11.2 deletion syndrome	TANGO2-related metabolic encephalopathy and arrhythmias
Delayed psychomotor development Impaired active speech development Epilepsy Divergent strabismus Reduced muscle tone Features of dysmorphia Heart defect (secondary ECG abnormalities due to cardiac surgery) Thymic agenesis Slightly decreased PTH levels (without evident hypocalcemia) Psychiatric symptoms (anxiety, mood disorder, behavioural differences, psychosis)	Delayed psychomotor development Impaired active speech development Epilepsy Divergent strabismus Reduced muscle tone Encephalomyopathic crises in medical history Rhabdomyolysis Lower limb pyramidal syndrome Poor motor coordination Dysphagia Drooling Abnormal acylcarnitine profile

The TANGO2 protein is functioning as a regulator in the organization of the Golgi apparatus and endoplasmic reticulum. Although its mechanism of action is not fully understood, it is postulated that its defect indirectly affects energy metabolism, including disturbances in fatty acid oxidation [6, 7]. Disorders in lipid homeostasis may manifest as nonspecific deviations in the acylcarnitine profile observed in patients with MECRCN, including the presented child [8, 9, 13].

The first symptoms of MERCN are observed in early childhood in most patients, often resulting in delayed or regressive psychomotor development and recurrent episodes of weakness similar to those observed in the presented girl [5, 8, 9, 13, 14].

Recurrent crisis associated with MECRCN are often preceded by infection. During these incidents, patients exhibit high values of biochemical markers associated with muscle breakdown (creatine kinase, transaminases, lactate dehydrogenase), as well as hypoglycemia, ketonuria, and increased ammonia levels. These parameters normalize after the crisis resolution [8, 9, 13]. Risk factors for metabolic deterioration may include also dehydration, fasting, excessive exertion, exposure to heat, ketogenic diet or certain anesthetic drugs [5, 9, 13, 15]. The described patient underwent two surgical procedures, and in both cases the perioperative period was uneventful, and the first occurrence of severe metabolic crisis in the described girl was accompanied by pneumonia. These findings may support that infection and the accompanying stress, increased energy demand, and associated reduced calorie intake constitutes is a greater risk factor for metabolic decompensation compared to the controlled stress of an elective surgical procedure.

Cardiac involvement, often revealed during metabolic crises, may manifest as long QT syndrome and lead to life-threatening arrhythmias, including torsades de pointes [5, 8, 9, 13]. The detected right bundle branch block was associated with the previous cardiac surgery, and no significant cardiac rhythm disturbances were observed, including QT interval abnormalities, were observed in our patient’s current observation. The absence of cardiac arrhythmia does not exclude the diagnosis, as it may not be present in all patients. Furthermore, the risk of future occurrence in our patient cannot be excluded.

Other symptoms mentioned include dysphagia, dysarthria, ataxia, pyramidal disturbances mainly affecting the lower limbs, cerebellar disorders, dyskinesias, or hearing impairments. Some patients, but not the presented girl, also have hypothyroidism [5, 8, 9, 13]. Progressive neurodegeneration can also lead to loss of speech expression. Lack of communicative speech development observed in our patient may be associated with both 22q11.2 microdeletion syndrome and MECRCN [1, 5, 8, 9].

In the differential diagnosis of lower limbs pyramidal syndrome, TANGO2-related disease should be considered alongside cerebral palsy, hereditary spastic paraplegia, and same inborn errors of metabolism including adrenoleukodystrophy, arginase 1 deficiency, biotinidase deficiency, cerebrotendinous xanthomatosis and hyperornithinemia-hyperammonemia–homocitrullinuria [16]. Cerebral palsy is characterized by the non-progressive nature of neurological deficits, typically with a medical history indicating perinatal complications and often with imaging findings suggestive of prior hypoxic-ischemic brain injury. Hereditary spastic paraplegia typically presents with progressive lower limb spasticity; similarly, in TANGO2-related disease, an intensification of spasticity may be observed with age [5, 16]. However, a key differentiating factor is that neither cerebral palsy nor HSP involves metabolic crises, which are a hallmark of TANGO2 deficiency. The occurrence of metabolic crises in a patient with pyramidal disorders also requires differentiation from other inborn errors of metabolism. While hyperornithinemia-hyperammonemia–homocitrullinuria syndrome, arginase 1 deficiency, and biotinidase deficiency may present with acute metabolic crises involving hyperammonemia or metabolic acidosis, the metabolic spells in TANGO2-related disease are uniquely characterized by profound rhabdomyolysis and the potential risk of life-threatening cardiac arrhythmias [5, 16].

Both mentioned genetic disorders are associated with epilepsy. The morphology of seizures can be generalized or focal [5, 8, 9, 17, 18]. In the presented child, seizures were characterized by sudden loss of awareness and generalized tonic–clonic motor activity, electroencephalography demonstrated generalized epileptiform discharges, and we revealed no focal structural abnormalities in brain magnetic resonance imaging. Based on the clinical and electrophysiological findings, and in the absence of evidence for focal onset, the seizures were classified as generalized tonic–clonic seizures. Treatment with levetiracetam resulted in complete seizure control.

Exotropia is also described in both conditions. In patients with MECRCN, it may worsen with fatigue [5, 9]. Other ophthalmic symptoms of MECRCN rarely include optic nerve atrophy [5, 8, 9]. In our patient, besides the identified exotropia, suspicion of drusen presence was raised, which has not been described in patients with TANGO2 gene variant before. In children, drusen are most commonly occult, leading to the blurring of optic nerve head boundaries, known as pseudoedema in ophthalmoscopic examination. Although these deposits often do not cause any symptoms, they may lead to changes in visual function and require periodic ophthalmic monitoring [1, 3, 19].

Despite the lack of thymus, the child presents with normal absolute number of T-cells with only minor decrease in naive CD4 + and increase in effector memory CD8 + T-cells. The overall CD4/CD8 ratio of 1.2 is however within the normal range. This observation may reflect the presence of compensating mechanisms taking over the T-cell production in peripheral lymphoid organs or in ectopically located thymus tissue [20].

The absence of hypocalcemia does not exclude the diagnosis of 22q11.2 deletion syndrome. Hypocalcemia may not be evident in the clinical history in some patients, as was observed in the presented girl. It may also occur episodically or manifest during periods of physiological stress, such as surgical procedures [1].

Due to the clinical presentation, particularly recurrent metabolic crises with rhabdomyolysis, the differential diagnosis of MERCN should include disorders of fatty acid oxidation. These conditions share features such as hypoglycaemia and episodes triggered by fasting or illness. However, defects in β-oxidation are characterized by typical abnormalities in the acylcarnitine profile (e.g., elevated C14:1 in very long-chain acyl-CoA dehydrogenase deficiency; in our patient with TANGO2 deficiency, increased C6 and C18:2OH acylcarnitines were observed), and reduced or absent ketone body production during crises. In contrast, acetonuria in this moment is often observed in TANGO2-related disease which may help distinguishes these conditions from MERCN-related disorders. The differential diagnosis should also consider mitochondrial diseases, selected glycogen storage diseases (types V, VII, IX, X, XI, and XIII), and lipin-1 deficiency [5, 13, 21].

Education of caregivers of children with MERCN is crucial. Patients require adequate hydration and nutrition, including the possibility of enteral nutrition through gastrostomy tube feeding, if necessary, avoidance of factors that may lead to metabolic crises, and prompt therapeutic intervention if symptoms occur. In the presented case, proactive gastrostomy placement may have played a key role in preventing subsequent metabolic crises by ensuring consistent hydration and caloric intake, thereby eliminating fasting episodes and dehydration, well-established triggers of metabolic decompensation in TANGO2 deficiency.

The 4-year crisis-free period following this intervention supports consideration of early gastrostomy placement as a preventive strategy in TANGO2 patients with any feeding difficulties, rather than a reactive measure after repeated crises. Furthermore, this case highlights the importance of expanding genetic testing more rapidly in children with microdeletion syndromes when clinical features are atypical or non-specific to the primary syndrome [10]. In our patient, three life-threatening metabolic crises occurred before exome sequencing was performed, a delay that could have been avoided had genetic testing been pursued after the first atypical presentation. Furthermore, periodic thyroid function monitoring, hormonal supplementation in case of hypothyroidism, antiseizure medication treatment in case of epilepsy diagnosis, and multidisciplinary follow-up including neurological, cardiological, ophthalmological, and audiological assessments are indicated [5].

Supplementation with coenzyme Q and carnitine (used due to a mitochondrial phenotype; however, there is currently no evidence of efficacy in TANGO2 deficiency or formal recommendations), and especially vitamin B complex (recommended at the minimum daily allowance for age) may have a beneficial effect on the course of the disease [5, 8, 9]. Particularly, vitamin B5 supplementation, which is a precursor of coenzyme A, may reducing the risk of encephalomyopathic crises [5, 6, 9]. Since the introduction of the above-mentioned dietary supplements in the presented patient, no metabolic crisis symptoms have been observed, and the parents reported improvement in the girl’s gait and cognitive abilities.

Conclusions

Despite the diagnosis of microdeletion 22q11.2, in cases with an atypical phenotype, further genetic diagnostics should be considered due to the possibility of additional hemizygous variant(s) in genes located on the remaining allele in 22q11.2 region such as variant in the TANGO2 gene. Critically, genetic testing should be expanded promptly when clinical features are non-specific or atypical for the primary syndrome, rather than delayed until multiple life-threatening events occur. In the presented case, exome sequencing was performed only after three metabolic crises over 2 years. Earlier testing after the first atypical presentation would have enabled timely initiation of preventive measures and potentially avoided subsequent crises.

Patients with TANGO2-related metabolic encephalopathy-arrhythmia syndrome require comprehensive and multidisciplinary care and treatment to reduce the risk of metabolic crises. Proactive nutritional support, including early consideration of gastrostomy tube placement in patients with any feeding difficulties, may play a crucial preventive role by ensuring consistent hydration and caloric intake and eliminating prolonged periods without nutrition, a well-established trigger of metabolic decompensation. The 4-year crisis-free period observed in our patient following gastrostomy placement suggests that this approach may serve as an effective preventive strategy and warrants further investigation in larger patient cohorts.

Abbreviations

TANGO2

Transport and Golgi organization 2 homolog

MECRCN

Recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias and neurodegeneration

ES

Exome sequencing

Biographies

Ewa Grzywna-Rozenek

Holds a PhD in Medical Sciences and is a pediatrician and pediatric neurologist at the Department and Clinic of Pediatrics, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice. Her research focuses on neurodevelopmental disorders and metabolic diseases in children.

Rafał Płoski

Professor Płoski is currently the Head of the Department of Medical Genetics at the Medical University of Warsaw. His research focuses on the application of advanced high-throughput DNA sequencing technologies in medical diagnostics. He is particularly involved in the development and implementation of modern genomic approaches to improve the diagnosis of genetic disorders and support precision medicine.

Robert Śmigiel

Professor Śmigiel is a specialist in pediatrics, neonatology, metabolic disorders, clinical genetics, endocrinology, and pediatric diabetology. He serves as the Head of the Department and Clinic of Pediatrics, Endocrinology, Diabetology, and Metabolic Disorders and is widely recognized as an expert in the diagnosis and management of rare genetic and metabolic diseases. He also serves as the Regional Consultant for Metabolic Disorders in the Lower Silesian Voivodeship.

Authors’ contributions

E.GR., M.S., R.Ś., K.BM. were involved in medical care of the patients, conceptualized the case report, drafted, reviewed, and revised the manuscript; M.R. and R.P. were involved in conduct, interpretation and visualization of genetic analysis and reviewed and revised the manuscript. A.BI. participated in data collection, draft the initial manuscript and conduct the literature research. Ł.S. was involved in conduct, interpretation and visualization of laboratory analysis and participate in draft the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Funding

Contract grant sponsor: SUBZ.C190.25.010 and 2023/ABM/02/00003 − 00.

Data availability

Data concerning the described patient are stored in the medical database of the University Clinical Hospital in Zabrze, Poland. They may be made available to reviewers by the corresponding author upon reasonable request.The variant was submitted to the Leiden Open Variation Database (LOVD v3.0) with the individual access number #00474343, available at: https://databases.lovd.nl/shared/variants#order=VariantOnGenome%2FDNA%2CASC&search_owned_by_=rydzanicz&page_size=100&page=1.

Declarations

Ethics approval and consent to participate

The study was submitted to the Bioethics Committee at the Wroclaw Medical University.

The Committee stated that, for this type of study, formal ethical approval was not required. The description of the patient includes an account of the diagnostic and therapeutic procedures carried out for the purpose of treating and improving the patient’s health.

The study was conducted in accordance with the principles of the Declaration of Helsinki.

Consent for publication

The legal guardians of the patient provided written informed consent for the use of information and images concerning their daughter for a scientific medical publication, free of charge and without time limitation.

Competing interests

The authors declare no competing interests.