Clinical case of Zhu–Tokita–Takenouchi–Kim syndrome

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Introduction

Zhu–Tokita–Takenouchi–Kim syndrome (ZTTK) is an extremely rare autosomal dominant disorder belonging to the group of nuclear speckleopathies, characterized by developmental delay and intellectual disability, with more than half of patients also experiencing seizures and behavioral issues. Speckleopathies are caused by alterations in the reference sequence of genes encoding proteins of nuclear speckles — nuclear bodies that regulate splicing.

To date, 87 patients with ZTTK syndrome have been described in the international literature.

Phenotypic manifestations of ZTTK include facial anomalies (asymmetry, ptosis, deep-set eyes, depressed nasal bridge, high palate, etc.), but these are not pathognomonic.

Skeletal and ocular anomalies, short stature, and genitourinary and renal abnormalities are frequently observed. Hematologic, cardiac, immune, and gastrointestinal disturbances, as well as hearing problems, have also been reported [1].

The primary cause of ZTTK syndrome has been identified as SON haploinsufficiency resulting from truncating variants or whole-gene deletions. SON encodes the RNA-binding protein SON and is constitutively expressed, although its expression is upregulated during early brain development. The SON protein is involved in pre-mRNA splicing (as a cofactor) and plays a key role in regulating pluripotency, the cell cycle, neurogenesis, and transcriptional regulation through its DNA-binding activity [2].

SON, located at 21q22.11, is a highly conserved gene that is ubiquitously expressed. The most common isoform consists of 12 exons. Haploinsufficiency of this gene can lead to intron retention and exon skipping, particularly at weak splice sites, affecting the function of numerous genes, including various genes involved in brain development, renal function, and metabolism. SON is involved in maintaining pluripotency and survival of embryonic stem cells, as well as in the alternative splicing of other genes involved in epigenetic regulation and apoptosis [3]. In addition, SON has been shown to participate in the transcriptional regulation of genes associated with carcinogenesis [4]. SON also plays an important role in mitochondrial function. Knockdown of SON expression causes widespread splicing defects. Among the transcripts most dependent on SON are genes responsible for the cell cycle, genome stability, and mitochondrial respiratory chain function and biogenesis of other mitochondrial proteins. This may explain why individuals with ZTTK syndrome can develop metabolic stroke. It is important to recognize that metabolic stroke may be a clinical manifestation of ZTTK syndrome, as this has clinical and therapeutic implications [5].

ZTTK syndrome is characterized by a broad spectrum of clinical manifestations. Most patients exhibit growth retardation, both prenatally and postnatally. Neurological findings include muscle hypotonia, less commonly hypertonia, seizures, electroencephalographic abnormalities, and congenital brain malformations. Cardiovascular defects, renal anomalies (horseshoe kidney and renal cysts), gastrointestinal abnormalities, visual and hearing impairments, recurrent otitis media, and immune system dysfunction have also been described [6].

Characteristic ocular features of ZTTK syndrome include deep-set eyes, downward-slanting palpebral fissures, and horizontally oriented eyebrows. Children with ZTTK syndrome may have visual problems, including optic atrophy and visual impairment leading to decreased visual responsiveness. Strabismus, deviation or crossing of the eyes when focusing on an object, simple hypermetropia, hyperopia, and nystagmus — repetitive and uncontrolled eye movements — are frequent manifestations of ZTTK syndrome [7].

Congenital defects such as thinning of the interatrial septum, ventricular septal defects, patent ductus arteriosus, renal dysplasia, and pulmonary and gallbladder agenesis have also been reported. Musculoskeletal anomalies observed in ZTTK patients include hemivertebrae, scoliosis or kyphosis, contractures, joint stiffness, joint hypermobility, and hypotonia. In the neonatal period, persistent feeding difficulties lead to growth retardation and short stature in most individuals with ZTTK syndrome [8]. Developmental delay is common in ZTTK syndrome and appears to exacerbate intellectual disability with age. Gross and fine motor development, as well as speech fluency and receptive language, lag behind age-appropriate norms. Macrocephaly and white matter abnormalities of the brain are also observed. Seizures often occur between 1 and 6 years of age [9]. Nearly all patients exhibit brain abnormalities on magnetic resonance imaging, with polymicrogyria (85%), corpus callosum abnormalities (77%), and ventriculomegaly (69%) predominating. A characteristic "figure-of-eight" appearance of the brain on axial sections has been described [10]. Electrocardiographic abnormalities include prolonged QT interval and bradycardia [11].

The aim of this study was to describe our own clinical observation of the ZTTK syndrome in an 8-year-old child.

Clinical case report

Patient S., Slavic, was born on November 13, 2017, from the second pregnancy (the first pregnancy was ectopic). The pregnancy was complicated by threatened miscarriage, oligohydramnios, iron-deficiency anemia, grade 1 fetal-placental blood flow impairment, intrauterine growth restriction, and chronic fetal hypoxia. The child was delivered by primary cesarean section at 35 weeks of gestation to a 31-year-old woman who was a carrier of herpes simplex virus, cytomegalovirus, Epstein–Barr virus, and toxoplasmosis. Birth weight was 1600 g, length 46 cm, head circumference 33 cm, and chest circumference 26 cm. Apgar score was 7/7. The child’s condition was severe due to respiratory failure, cerebral ischemia, and prematurity. The boy was transferred to the intensive care unit, where he received respiratory support with CPAP (Continuous Positive Airway Pressure) for 7 days, antibacterial therapy (bacperazone, amikacin, diflucan, sultasin), anti-hemorrhagic therapy (sodium etamsylate), anti-anemic therapy (actiferrin, folic acid, vitamin E), and parenteral nutrition. Subsequently, the patient was transferred to the premature infant pathology department with the following diagnoses: acute intestinal obstruction; ulcerative-necrotic enterocolitis; intussusception; right-sided inguinal hernia. Prematurity at 35 weeks. Grade 3 intrauterine growth restriction of hypotrophic type. Grade 2 cerebral ischemia with vegetative-visceral dysfunction syndrome; grade 2 intraventricular hemorrhage. Congenital infection: congenital right-sided unspecified pneumonia, convalescent; patent foramen ovale. Severe anemia of prematurity, status post-blood transfusion. Transient thrombocytopenia; bilateral pyelectasis. At risk for hearing loss.

The child has been followed by a neurologist since birth due to motor developmental delay: he held his head at 7 months, rolled from supine to prone at 8 months, began sitting at 1 year 3 months, crawled on his belly at 1 year 6 months, on all fours at 1 year 8 months, stood with support at 1 year 9 months, and walked independently from age 4, with an unsteady gait and frequent falls. Psychomotor and speech development was also delayed: first words appeared at 3 years, and phrase speech at 5 years. He has difficulties with fine motor skills; self-care skills are established. He attends a preschool facility but does not play with other children and avoids them.

Ultrasound of the cervical sternocleidomastoid and paraspinal muscles (February 14, 2018) revealed signs of bilateral spasticity of the sternocleidomastoid muscles.

Three neurosonography studies performed between February and May 2018 revealed a persistent pattern of bilateral intraventricular hemorrhage with ventricular dilatation (predominantly on the left initially, and later bilateral), accompanied by cerebrospinal fluid circulation disturbances. Over time, improvement was noted: the hemorrhage gradually entered a residual phase. However, progressive dilatation and the formation of a small arachnoid cyst were also observed.

Tandem mass spectrometry (June 22, 2018) showed normal activity of the lysosomal enzymes tested, ruling out a range of metabolic disorders. Electromyography (September 4, 2018) revealed signs of primary muscle involvement with suprasegmental regulatory impairment. Brain magnetic resonance imaging (MRI) (October 23, 2018) confirmed moderate dilatation and asymmetry of the lateral ventricles, clinically interpreted as hypertensive-hydrocephalic syndrome, with no signs of brainstem displacement.

Between 2019 and 2023, serial electroencephalograms (EEGs) showed a persistent, moderately pronounced pattern of generalized cerebral changes in bioelectrical activity. Key dynamic features included the gradual emergence and evolution of epileptiform activity with initially slow and irregular cortical rhythms. By early 2022, periodic slowing and isolated epileptiform elements began to appear in the centroparietotemporal regions, particularly during sleep. By mid-2022, the pattern was supplemented by bursts of high-amplitude beta activity with spikes in the frontotemporal leads (predominantly on the left) and bilateral slow waves during sleep onset. By 2023, despite a low index (less than 1–3%), epileptiform activity became a consistent finding, shifting its localization from the left centroparietal regions to the right frontotemporal lobes, with spike-wave discharges recorded during sleep.

Video-EEG monitoring during sleep (July 31, 2024) revealed changes in bioelectrical activity manifested as isolated bursts of sharp and pointed slow waves in the frontocentral and temporal regions with periodic regional delta slowing.

Neurological status changes: The patient had generalized muscle hypotonia since birth. At 2–3 years of age, against the persistent hypotonia, the first signs of postural instability appeared during attempts at verticalization. By age 4, when the child began to walk independently, a mixed (cerebellar-sensory) ataxia had developed, with marked gait unsteadiness, frequent falls, and impaired balance in the Romberg position. Between 4 and 6 years of age, there was a gradual increase in ataxia: coordination in finger-to-nose and heel-to-knee tests worsened, and intention tremor appeared during goal-directed movements. From age 5, a pyramidal syndrome began to develop, manifesting as increased deep tendon reflexes (knee, Achilles) with expanded reflexogenic areas and foot clonus. Muscle tone became dystonic with fluctuations, predominantly in the distal upper limbs and axial muscles, without overt hyperkinesias (chorea, athetosis, tremor). From age 6, a slowing in the acquisition of new motor skills was noted, with worsening fine motor difficulties (trouble buttoning clothes, grasping small objects), interpreted as progression of coordination and pyramidal deficits. Psychomotor and speech development also showed negative changes: after phrase speech developed by age 5, from age 6 there was a reduction in active vocabulary, decreased speech activity, and the emergence of motor alalia elements. Behavioral disturbances appeared from age 5, including increasing anxiety, stereotypies, and avoidance of peer contact.

In 2023, he was evaluated by an orthopedic traumatologist with complaints of gait unsteadiness and coordination challenges. A diagnosis of bilateral hip dysplasia grade 2 and plano-valgus foot deformity was made.

In January 2024, at age 6, the patient was evaluated by a geneticist at the Bochkov Medical Genetics Research Center (Moscow). Differential diagnosis was conducted within the group of Noonan syndrome and Noonan-like syndromes (Noonan, LEOPARD, Costello, Legius, cardiofaciocutaneous syndrome, and RAS-associated autoimmune lymphoproliferative syndromes). Panel sequencing for the genes PTPN11, SOS1, RAF1, RIT1, HRAS, KRAS, NRAS, BRAF, MAP2K1, MAP2K2, SPRED1, LZTR1, CBL, SHOC2, and SOS2 revealed no mutations.

In May 2025, at the age of 7 years, the patient was evaluated by a geneticist at the Regional Children’s Hospital in Lipetsk. The findings included psychomotor and speech developmental delay, visual impairment, gait disturbance, reduced tone in the upper and lower extremities, and the presence of café-au-lait spots. In July 2025, brain MRI (performed in Lipetsk) revealed an abnormal lesion in the right thalamus (Figure 1), prompting differential diagnosis with neurofibromatosis type 1. For further clarification, a consultation was arranged at the Pirogov Russian National Research Medical University.

 

Fig. 1. Brain MRI of patient S.

The red arrow indicates the lesion.

 

Contrast-enhanced MRI (Lipetsk, October 27, 2025): a focus of increased MR signal on T2-weighted and T2-FLAIR images, measuring 5.5 × 4.0 mm, was identified within the right thalamus, at the level of the ventral lateral nucleus, with no diffusion restriction or SWI changes. The cerebellar tonsils were at the borderline of the foramen magnum. Mild dilatation of the lateral ventricles persisted (S > D) at the level of the bodies, measuring 13 mm and 10 mm, respectively. The pituitary gland was small, with adenohypophysis height of 2.0–2.2 mm; the suprasellar cistern showed mild herniation into the sella turcica. No abnormal contrast accumulation was observed in the right thalamic lesion or in the cerebral or cerebellar parenchyma.

According to available data, there is currently insufficient evidence for a diagnosis of neurofibromatosis type 1.

Physical examination (October 23, 2025): Height 122 cm (–0.68 SD), weight 21 kg (–1.44 SD). Facial phenotype: thick, dark arched eyebrows, bilateral epicanthus, ptosis, flattened philtrum, Cupid’s bow-shaped upper lip, and posteriorly rotated ears. Pronounced valgus deformity of the right foot.

In April 2024, whole-exome sequencing revealed a heterozygous nucleotide variant in the SON gene: chr21:33549607GA>G (c.384delA, p.Lys128fs). The pathogenicity of this variant has been confirmed and registered in the ClinVar international database.

Sanger sequencing of the SON gene (January 19, 2026): a heterozygous nucleotide variant in exon 3 of the SON gene (chr21:33549607GA>G; ENST00000356577:c.384delA:p.Lys128fs) was identified in the patient’s sample. This heterozygous mutation is associated with ZTTK syndrome, with autosomal dominant inheritance. A clinical diagnosis of ZTTK syndrome was established. This variant was not detected in the maternal or paternal samples.

Somatic status (January 30, 2026): Height 123 cm, weight 22 kg. Irregular body habitus. Two small café-au-lait spots were present on the skin of the hands and trunk. Multiple stigmata of dysembryogenesis were noted.

Neurological examination revealed dysarthria, divergent strabismus, diffuse muscle hypotonia, pathological plantar reflexes, and moderate statolocomotor ataxia of mixed (cerebellar and sensory) type.

Thus, this case demonstrates the classic phenotype of ZTTK syndrome, confirmed by molecular-genetic testing and Sanger sequencing. The c.384delA (p.Lys128fs) mutation identified in the patient results in a frameshift and premature stop codon, leading to the synthesis of a truncated non-functional protein or triggering nonsense-mediated mRNA decay. This results in haploinsufficiency of the SON protein — a key regulator of pre-mRNA splicing, neurogenesis, and maintenance of cellular pluripotency. The major pathophysiological manifestations of the syndrome — psychomotor developmental delay, structural brain anomalies (corpus callosum hypoplasia, cortical dysplasia), muscle hypotonia, and characteristic facial dysmorphism — are attributed to the disruption of these fundamental processes [3, 12].

In a Russian study (2024), the authors described three patients with ZTTK syndrome in Russia. Among the three identified variants, one — c.403delG (p.Glu135Asnfs*14) [13] — is adjacent to our case (a deletion in the same exon, 19 amino acids away). Our variant (c.384del) was not described in that study. Long-term follow-up over several years allowed documentation of the natural progression of the disease. Neurological deficits increased in a stepwise manner: at 2–3 years of age, with initial generalized hypotonia, postural instability began to emerge; by age 4, mixed (cerebellar-sensory) ataxia developed, which progressed between 4 and 6 years, manifesting as worsening coordination and intention tremor. From age 5, a pyramidal syndrome developed (increased deep tendon reflexes, foot clonus), and muscle tone became dystonic with fluctuations, predominantly in the distal upper limbs and axial muscles. Concurrently, from age 6, a slowing of fine motor development was noted, along with negative speech dynamics, including reduced active vocabulary and decreased speech activity. Bone deformities (plano-valgus foot deformity, hip dysplasia) were identified at age 6 and were non-progressive at the last examination. The patient exhibits the classic triad of the syndrome: severe psychomotor developmental delay, muscle hypotonia, and specific facial dysmorphism. The lesion identified in the right thalamus, given its characteristics (no contrast enhancement, diffusion restriction, and progression), is highly likely to be residual or congenital in nature. In a patient with ZTTK syndrome caused by a mutation in the SON gene, which plays a key role in neurogenesis, a dysontogenetic origin of this lesion appears most plausible.

This case illustrates the need to include ZTTK syndrome in the differential diagnosis when developmental delay, hypotonia, and multiple stigmata of dysembryogenesis are present. Early implementation of whole-exome sequencing in the diagnostic algorithm is a critical tool for reliable verification of genetic pathology and reducing the duration of the multi-component differential diagnostic workup. Although no pathogenetic treatment is available, palliative and rehabilitative care remain the cornerstone of management for patients with this rare condition. Descriptions of such cases expand our understanding of long-term prognosis and contribute to the development of standardized follow-up protocols for patients with nuclear speckleopathies.

About the authors

Natalya A. Belykh

I.P. Pavlov Ryazan State Medical University

Email: innaabramova@yandex.ru
ORCID iD: 0000-0002-5533-0205

Dr. Sci. (Med.), Head, Department of Outpatient Pediatrics

Russian Federation, Ryazan

Maria D. Krukovskaya

I.P. Pavlov Ryazan State Medical University

Email: innaabramova@yandex.ru
ORCID iD: 0009-0008-1846-3798

6th-Year Student, Faculty of Pediatrics

Russian Federation, Ryazan

Georgy B. Krukovsky

I.P. Pavlov Ryazan State Medical University

Email: innaabramova@yandex.ru
ORCID iD: 0009-0001-2796-2037

6th-Year Student, Faculty of Pediatrics

Russian Federation, Ryazan

Inna V. Piznyur

I.P. Pavlov Ryazan State Medical University

Author for correspondence.
Email: innaabramova@yandex.ru
ORCID iD: 0000-0002-9267-439X

Assistant, Department of Faculty and Outpatient Pediatrics

Russian Federation, Ryazan

Anastasia S. Zhdankina

Regional Children's Hospital, Lipetsk

Email: innaabramova@yandex.ru
ORCID iD: 0009-0005-3941-1020

Neurologist, Pediatric Neurology Department

Russian Federation, Lipetsk

References

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