Lesch-Nyhan disease (LND) is a rare X-linked recessive genetic disorder associated with purine metabolism dysfunction . It was first described at Johns Hopkins Hospital in 1964 by Lesch and Nyhan . The prevalence is estimated at 1/380,000 live births in Canada and 1/235,000 in Spain, respectively . It presents severe dystonia, gout, intellectual disability, short stature, attention deficit, and self-mutilation [4,5].
On the other hand, neurofibromatosis type 1 (NF1) is a relatively common autosomal dominant genetic disorder. It is a multisystem disorder which attributes to the development of benign or malignant tumors in various systems, mainly in the nervous system . Most commonly associated tumors include optic glioma, glioblastoma, gastrointestinal stromal tumor, leukemia, pheochromocytoma, breast cancer, and rhabdomyosarcoma . It was first described by German pathologist Friedrich von Recklinghausen in 1882 . About 1 in 2,500-3,000 people worldwide, irrespective of ethnicity or sex, are affected by the disease . Patients with NF1 can manifest cognitive impairments including language and memory, behavioral problems, attention deficits, and problems with executive functions, and motor skills .
Here we report a rare case of a patient who has inherited two genetic mutations from his mother that leads to co-existing two diseases from these mutations.
This study was approved by the Institutional Review Board (IRB) of Soonchunhyang University Bucheon Hospital (IRB no. SCHBC 2022-05-006). The patient’s parents provided written informed consent for the publication of this case report including patient information.
A 5-year-old boy was referred to our hospital for hyperuricemia and severe neurodevelopmental impairment. He was born at 39 weeks of gestation and birth weight of 3,140 g via spontaneous vaginal delivery without perinatal problems. His father and older brother were healthy without any diseases. His mother was diagnosed with NF1 but had no intellectual disabilities (Fig. 1). Because he had typical multiple café au lait macules like his mother, he was clinically suspected of NF1. Additionally, he also showed head lagging even after 8 months after birth. He was then diagnosed with NF1 by genetic testing. He underwent regular physical and occupational rehabilitation. When he was 2 years old, hyperuricemia was observed and he started taking allopurinol continuously.
When he was 5 years old, he visited our hospital for accurate evaluation and treatment of hyperuricemia and severe developmental impairment. He was 120.9 cm in height (>97 percentile in the Korean national growth chart) and 13 kg in weight (<3 percentile). He showed multiple café au lait macules scattered on his whole body but there was no visible neurofibroma on his skin, unlike his mother. He was able to crawl on his stomach and stand still for a while with his arms supported. Also, he showed neurologic symptoms such as dystonia, rigidity, and involuntary movement.
His laboratory test result showed that he has significantly elevated serum uric acid levels despite continuous treatment. He also showed punctate high echogenic foci of the left kidney and right upper pole kidney, mainly in the renal sinus and medullary portion, which suggests nephrocalcinosis in kidney ultrasonography. The patient and his mother underwent a whole-exome sequencing (WES) to determine the exact cause of his neurologic symptoms and hyperuricemia. As a result, the variant c.151C>T (p.Arg51Ter) in hypoxanthine-guanine phosphoribosyltransferase (
At 5 years old, he had the first seizure in about an hour and took levetiracetam orally for about a year. After that, there were no seizures and the electroencephalogram was normal, so he stopped taking an anticonvulsant. Also, he underwent brain magnetic resonance imaging. Mild aneurysmal change in the right distal internal carotid artery and multiple subtle T2 high-signal intensity scattered lesions including pons, bilateral basal ganglia, thalamus, and cerebellar white matters were found, which were suspected to be related to NF1. An ophthalmologic examination was performed for NF1-related ocular signs, but there were no abnormal findings.
At 7 years old, his developmental delay was evaluated by Korean Developmental Screening Test for Infants & Children (K-DST), which is designed to assess gross motor skills, fine motor skills, cognitive development, social development, and language development. He obtained the lowest grades in every area in K-DST for his age. He could only stand still for a limited time and not walk alone without support. He could only speak a few words like “Mama” or “Papa”. Recently, he started to grind his teeth occasionally, but he has not yet shown typical self-mutilation.
Now, he continues to take sodium bicarbonate and allopurinol. His serum uric acid levels are well within the normal range so far. Also, he is doing more comprehensive rehabilitation including occupational, physical, cognitive, and Vojta rehabilitation.
LND is a rare X-linked recessive genetic disorder associated with dysfunction of purine metabolism . Clinical manifestations of LND include severe dystonia, gout, intellectual disability, short stature, attention deficit, and self-mutilation [4,5].
Patients with LND usually have normal prenatal and perinatal histories. The most common initial findings during the first year of life are delayed motor skills and hypotonia. Children with LND fail to achieve normal milestones such as sitting, crawling, and walking. Within the first few years of life, abnormal movements emerge, especially severe action dystonia which resembles dyskinetic or athetoid cerebral palsy. Most patients with LND have neurodevelopmental impairment whose severity usually ranges from mild to moderate, rarely severe .
The most typical and remarkable symptom that makes clinicians suspicious of LND is self-mutilation. Self-mutilation in LND patient usually begin to manifest after 1 year of age, especially perioral self-mutilation as their teeth come in. The behavior continues and can lead to the partial or total destruction of perioral tissue, and amputation of fingers, toes, and tongue . In this case, the patient did not show this symptom until the age of 5, so the diagnosis of LND was delayed.
LND has a defect in the purine salvage pathway, so patients have elevated uric acid levels in their serums. It is commonly treated using allopurinol to mitigate uric acid overproduction but it seems ineffective in neurobehavioral symptoms. In one study, a prenatally diagnosed LND patient who was administered allopurinol upon birth and never had elevated uric acid levels still developed neurobehavioral impairment, while it is effective in treating gout and liver failure . Since its first description in 1964, several therapeutics, including dopaminergic agents, deep brain stimulation, and S-adenosylmethionine, have been tried for the treatment of LND. Although some progress has been made, many LND patients and their families still do not receive effective treatment today .
While the mutations are widely distributed throughout the
NF1 is a relatively common autosomal dominant genetic disorder. It is a multisystem disorder which attributes to the development of benign or malignant tumors in various systems, mainly in the nervous system. Clinical manifestations in NF1 are extremely variable including cognitive impairments, behavioral problems, attention deficits, and problems with motor function, executive function, and language, specific dermatological findings such as Café au lait macules, skinfold freckling, and Lisch nodules. Many NF1 patients develop only cutaneous manifestations and Lisch nodules. The frequency of other complications tends to increase with age. Although NF1 patients have nearly normal intelligence in general, behavioral problems and learning disabilities are commonly seen in 50-80%. Intellectual disability is seen in 6-7%, which is about twice that in the general population [14,15]. Features of autism spectrum disorder occur in up to 30% of children with NF1 . Germline mutation of the
NF1 has extreme clinical variability, not only between unrelated individuals and among affected individuals within a single family but even within a single person at different ages in life. The detection of mutations in the
Treatment is individualized on the clinical symptoms of the patient. Dermatologic findings such as Café-au-lait macules, skinfold freckling, and Lisch nodules have no malignant potential that dermatological camouflage is useful for cosmetic purposes. Tumorous lesions can vary and treatment should be individualized according to the characteristics of the tumor. Surgical removal, radiation therapy, and chemotherapy can be an option. There is no established pharmacological method to improve neurodevelopmental impairment in NF1 patients. Recent research on lovastatin showed the beneficial effects of this medication on some cognitive functions related to learning and memory by acting on synaptic plasticity. Methylphenidate has shown benefits by decreasing attention-deficit-hyperactivity-disorder symptoms . But these drugs need further study to prove their clinical effectiveness and long-term safety when used in NF1 patients.
Due to the rarity of LND, cases of patients with LND who also have NF1 simultaneously have not yet been widely reported and their association has also not been unveiled. So here we report a rare case of a patient who has inherited two genetic mutations from his mother and has co-existing two diseases from these mutations. In this case, we speculate that these two mutations may have occurred by chance in the patient’s mother without any correlation as their causative genes are located differently.
The patient showed severe neurodevelopmental impairment. We suppose that this severe intellectual disorder may be affected by the co-occurrence of these two diseases. As clinical symptoms of these two diseases seem to be overlapped clinically and manifest in a mixed form, his neurodevelopmental problems are not well distinguished in their origin. As it is not well known how these diseases affect clinical courses of each other, further study is needed. We believe that it is worthwhile tracking the clinical course of this rare case to understand the clinical course in the special situation that these two different diseases co-exist simultaneously and their possible synergistic effect on impairing patients’ neurodevelopment.
In this case, hyperuricemia and severe developmental delay, which is not well explained by the only presence of NF1, made us do further evaluation including WES, and it led to the discovery of a new disease that was previously unknown. It helped us to understand the patient much better and to individualize treatment for the patient. From this point, we suppose that in the complicated mixture of symptoms in the patient of a rare genetic disease, unpredicted symptoms that are not well explained by the only presence of a previously known disease can sometimes justify the need for further evaluation. So we suggest considering a preemptive genetic evaluation if there are symptoms that are not fully explained by known, existing diseases as in this case.
The authors declare that they do not have any conflicts of interest.
Conception and design: JHY. Acquisition of data: YLS. Analysis and interpretation of data: YLS, GHS. Drafting the article: JHY, YHH, YLS. Critical revision of the article: JHY, YLS. Final approval of the version to be published: all authors.