Case Report: Pre- and post-natal evolution of Kabuki Syndrome due to a novel genetic mutation

Fetal period

The mother was twenty-nine years old, Para 0, Gravida 1, with no familial history of genetic abnormalities or intellectual defect. She was referred by a private gynecologist to the Department of Gynecology and Obstetrics at Ben Arous Regional Hospital following the discovery at 26 weeks’ gestation of ventriculomegaly with bilateral pyelectasis. The pregnancy follow-up was irregular, and the mother didn’t undergo first-trimester combined screening for chromosome abnormalities.

Ultrasound performed at our department showed bilateral colpocephaly associated with an enlarged cavum pellucidum (Figure 1). Furthermore, biometric measurements did not reveal intrauterine fetal growth restriction. All tests for common infectious diseases such as Toxoplasmosis, syphilis, varicella-zoster virus, parvovirus B19, Rubella, Cytomegalovirus, and Herpes simplex virus come back negative.

Figure 1. Prenatal ultrasonography performed at 26 weeks of gestation showing occipital horns dilatation (colpocephaly).

A fetal Magnetic Resonance Imaging (MRI) was performed at 28 weeks’ gestation, confirming the diagnosis of agenesis of the corpus callosum associated with ventriculomegaly, without other associated malformations, particularly no other abnormalities to the brain (Figure 2).

Figure 2. Fetal Magnetic Resonance Imaging (MRI) performed at 28 weeks gestation, confirming the diagnosis of agenesis of the corpus callosum associated with ventriculomegaly.

An amniocentesis was performed after parental consent to obtain standard karyotype, which showed a normal male 46, XY chromosomal formula.

A meeting was organized with the parents, involving gynecologists and pediatricians, to discuss the possible origins of the anomalies and their associated prognosis. The parents decided to continue the pregnancy to term without any further investigations.

Neonatal period

The patient was born vaginally at 37 weeks’ gestation with good adaptation to extrauterine life. Upon initial examination, he was eutrophic with a weight of 3050 g, length of 49 cm, and head circumference of 34 cm. He exhibited facial dysmorphology, including a flat occiput, prominence of the metopic suture, an oval-shaped face with a narrow forehead, large almond-shaped eyes, and intermittent convergent strabismus of the left eye. Examination of the limbs revealed flat feet, without any other musculoskeletal malformations. However, upon examination of the external genitalia, no gonads could be palpated.

He was initially hospitalized for transient respiratory distress, which resolved within 48 hours. A grade 3 murmur was also detected upon cardiac auscultation at the aortic area. Upon examination of the external genitalia, gonads were not palpable. The neurological examination was unremarkable.

From birth to the age of 7 years

The patient’s facial dysmorphology became more evident at the age of 4 years and 9 months. It was characterized by a flattening of the occiput, marked microcephaly at (-2) standard deviations (SD) with prominence of the metopic suture, and an oval-shaped face with a narrow forehead. The eyes showed sparse outer halves of both eyebrows, increased eye size with heavy eyeliner, intermittent convergent strabismus of the left eye, inversion, or eversion of the lower eyelids on both sides, forward-tilted nostrils, a mildly marked philtrum with notable depression at the root and tip of the nose (Figure 3). The ears were wide and protruding, with outwardly turned earlobes. In the oral cavity, there was a high-arched palate, a small mouth with a thin upper lip, and micrognathia (Figure 3). In the limbs, bilateral brachydactyly of the hands was observed (Figure 4a) but radiological examination did not provide evidence supporting this finding (Figure 5). Hypoplastic nails of the 5th fingers and toes, bilateral persistence of fetal fingerprints, and ligamentous hyperlaxity with loose skin were also noted (Figure 4 a,b).

Figure 3. Facial dysmorphia showing depression at the root and tip of the nose, wide and protruding ears, with outwardly turned earlobes, high-arched palate, a small mouth with a thin upper lip, and micrognathia (Written informed consent for publication of the patient’s clinical images was obtained from the patient’s legal guardian).

Figure 4. Limb abnormalities: Hypoplastic nails of the 5th fingers and toes, bilateral persistence of fetal fingerprints, loose skin.

a: Bilateral brachydactyly of the hands; b: Hypoplastic nails of the 5th fingers and toes, bilateral persistence of fetal fingerprints, and ligamentous hyperlaxity with loose skin.

Figure 5. Hand X-ray performed at the age of 4 years 9 months showing no radiological evidence of brachydactyly.

In terms of psychomotor development, there was a slight delay in achieving a sitting position at nine months and walking at eighteen months. Speech therapy evaluation revealed nasal speech with a slight delay in language acquisition, with the patient starting to form short phrases at the age of three.

Neurological investigations showed agenesis of the corpus callosum on transfontanellar ultrasound performed on day 32 of life. Given these lesions and the flat occiput, the diagnosis of Crouzon syndrome was suspected, which also remains a differential diagnosis of Kabuki syndrome. A subsequent brain CT-scan revealed a complete agenesis of the corpus callosum, associated with dilation and enlargement of the occipital horns of the lateral ventricles, colpocephaly, distortion of the frontal horns of the lateral ventricles resembling the appearance of bull horns, and ascent of the roof of the third ventricle. Partial filling and hypoplasia of the maxillary sinuses and agenesis of the frontal sinuses were also observed, with no signs of craniofacial dysostosis. A brain Magnetic Resonance Imaging confirmed the total agenesis of the corpus callosum, with an eccentric appearance of the lateral ventricles and bilateral dilations of the occipital and temporal horns.

Regarding neurosensory evaluations, an ophthalmological examination performed under general anesthesia revealed visual acuity of 5/10 with correction in the right eye and 7/10 in the left eye, along with convergent strabismus in the left eye. Auditory-evoked potentials were found to be normal.

On the therapeutic level, speech therapy intervention was carried out, and the following results were observed after rehabilitation: Currently, the patient presents with logorrhea, some pronunciation difficulties, and a normal IQ. He presents a significant improvement in communication, good comprehension of simple instructions, good acquisition of oral and written language, and no contraindications for school inclusion. The recommended approach and therapeutic plan included parental initiation and guidance, referral to a specialized center or other specialties for school integration, continued speech therapy, and recommended consultations with child psychiatry.

In terms of growth and weight, the patient experienced stature growth retardation with a deviation from the growth curve at the age of 5 years (Figure 6). Bone age evaluation performed at the chronological age of 5 years revealed a 2-year lag compared to the chronological age, suggesting a possible endocrine cause. Blood tests showed Thyroid-stimulating hormone (TSH) at 1.88 μIU/ml (0.35-4.94 μIU/ml), Thyroxin (FT4) at 13.97 pmol/l (9-19 pmol/l), cortisol level at 140 ng/ml (100-240 ng/ml), Adrenocorticotropic hormone (ACTH) at 28.6 ng/l (7.2-63.3 ng/l), Insulin Growth factor 1 (IGF1) at 87.53 ng/ml (associated with normal liver function), insulin stimulation test for Growth hormone (GH) secretion at 4.63 ng/ml (>20 ng/ml). The diagnosis of growth hormone deficiency was established. A Magnetic Resonance Imaging (MRI) of the hypothalamus-pituitary region showed no abnormalities. The patient was started on injectable growth hormone therapy at a dose of 0.030 mg/kg/day subcutaneously, with good progress (average height gain of 7.5 cm per year) (Figure 6).

Figure 6. Height versus age curve showing stature growth retardation with a deviation from the growth curve at the age of 5 years followed by a satisfactory response to hormone therapy with the growth hormone.

Regarding the respiratory tract, the patient had recurrent episodes of bronchiolitis associated with pneumonia, with a frequency of two infections per year. The latest episode was at the age of eight years old. An initial immunodeficiency workup returned normal.

Regarding the cardiac aspect, the cardiac ultrasound performed at birth revealed a restrictive subaortic ventricular septal defect without significant impact on the heart. Subsequent echocardiographic evaluations showed the same aspect of the ventricular septal defect (VSD), and periodic monitoring was recommended without the need for surgical intervention. Currently, he presents with a small VSD without any significant impact.

The anomalies identified during the prenatal ultrasound have been confirmed. An abdominal ultrasound performed at the age of one month revealed left renal megacalycosis. A follow-up ultrasound at the age of one year showed left pyelectasis with anterior-posterior pyelic diameter (APPD) of 16mm, without visible obstruction, consistent with pyelo-ureteral junction syndrome. A renal scintigraphy performed at the age of 4 years showed left pyelectasis with satisfactory non-obstructive drainage and symmetrical renal function. The right kidney showed early perfusion and uptake with delayed drainage, responding fully to Lasix injection, with an estimated relative function of 48%. The left kidney showed normal perfusion and uptake, with pyelectasis and delayed drainage responding to Lasix injection, with an estimated relative function of 52%. A retrograde uretero-cystography was performed, and showed no abnormalities, particularly no passive or active vesicoureteral reflux. The patient is currently being followed up in pediatric surgery. He did not experience urinary tract infections.

Additionally, in the presence of empty scrotum, testicular ultrasound revealed two inguinal testicles. He underwent surgery without any complications.

As part of the genetic investigation, a postnatal karyotype was performed, resulting in 46, XY normal formula. To confirm the diagnosis, DNA extraction was carried out and high-throughput sequencing using the MiSeq sequencer was performed, thanks to a custom panel containing genes implicated in Kabuki syndrome as described in the literature. Subsequently, bioinformatic analysis was completed for variant annotation, filtration, and classification. A variant in the KMT2D gene (NM_003482.4): c.11782C>T (p.Gln3928Ter) was identified, representing a likely pathogenic class 4 missense point mutation according to the recommendations of the American College of Medical Genetics and Genomics (ACMG) (Figure 7).

Figure 7. The genomic region where the KMT2D mutation variant (NM_003482.4): c.11782C>T (p.Gln3928Ter) is located (a point mutation by substitution in the KMT2D gene).