Primary Ciliary Dyskinesia and Hydrocephalus With Aqueductal Stenosis

Case Report

Our patient was a female, the first child of healthy, second-degree consanguineous parents of Gypsy ethnic origin. There was no family history of congenital malformations or of neurologic disease. The mother had not been exposed during pregnancy to tobacco smoking, alcohol, ionizing radiation, or drugs, either prescription or illicit, and had no intercurrent febrile illnesses or gestational diabetes. She had regular medical surveillance by her primary care practitioner without any apparent complication until the 21st week. Fetal ultrasound was performed at this time and revealed cardiomegaly without signs of congestive heart failure. She was then referred to our obstetric unit; serial fetal echocardiograms were performed every 2 weeks and revealed congenital atrioventricular block and a possible right heart malformation. Extensive laboratory investigations failed to reveal any autoimmune or infectious disease during pregnancy.

The child’s delivery was at 38 weeks by elective cesarean section. This female newborn had a birth weight of 3040 g, length 48.1 cm, and head circumference 35.0 cm. Apgar score was 8 at 1 minute and 9 at 5 minutes but, because of persistent bradycardia due to atrioventricular block, she was admitted to our neonatal intensive care unit. Cardiologic evaluation revealed a complex heart malformation (dextrocardia, common atrium, and patent ductus arteriosus); the patient also had situs inversus totalis and intestinal malrotation and was transferred to the pediatric cardiology unit. At 35 days of age, 12 days after elective cardiac surgery, she was in cardiorespiratory failure, dependent on mechanical ventilation, had infectious endocarditis, and required major abdominal surgery because of necrotizing enterocolitis. Neurologic evaluation was then requested because further efforts at treatment were considered to be dependent, at least partially, on prognosis regarding neurologic function.

There were no facial or limb malformations. Anterior fontanel was slightly tense. Sutures were not diastatic. Head circumference was 36 cm. Despite being sedated, the child had periods of wakefulness and moved the limbs symmetrically. Cranial nerve examination was normal. Tone was slightly increased in the lower limbs and reflexes were brisk. Ankle clonus was not present.

Because of the possible abnormal tension of the fontanel, a computed tomographic (CT) scan was performed and revealed a triventricular hydrocephalus. The lateral and third ventricles were visibly enlarged (Figure 1A and B). The fourth ventricle was small (Figure 1C). Hydrocephalus seemed to be low grade or arrested because there was no periventricular hypodensity related to transependymal reabsorption of cerebrospinal fluid. No other central nervous system abnormalities were apparent.

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Figure 1.

(A) Head computed tomographic (CT) scan showing hydrocephalus with dilated lateral ventricles. (B) Head CT scan showing dilated lateral and third ventricles. (C) Head CT scan showing dilated temporal horns of the lateral ventricles and small fourth ventricle.

The patient’s nasal mucosa cells were studied ultrastructurally and showed abnormal cilia consistent with a diagnosis of primary ciliary dyskinesia (Figure 2).

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Figure 2.

(A) Scheme of normal ciliary ultrastructure. (B) Electron microscopic image of the patient’s respiratory epithelium cilia showing abnormal microtubules with absent inner and outer dynein arms.

Despite all efforts, the child died at the age of 182 days of cardiorespiratory failure. Only some exons of the DNAI1 and DNAH5 genes were investigated because DNA available for these studies was insufficient; no mutation was found.

Discussion

Ciliary motility is needed for the determination of right-left asymmetry during embryonic development, for the adequate functioning of epithelial cells of the respiratory tract, and for the motility of gamete. More recently, there is also evidence that the function of the retina, liver, and kidneys is also affected by abnormal cilia. ¹

Neuropathologic studies of hydrocephalus reveal that increased intraventricular pressure causes damage to ependymal cells and disturbs ciliary function. ¹⁰

There is nevertheless convincing evidence from experimental studies of hydrocephalus in mice with ciliary dyskinesia that ciliary dysfunction is, in these cases, the cause rather than the consequence of hydrocephalus probably because ciliary beating is needed for cerebrospinal fluid flow, especially in the aqueduct of Sylvius. In addition, in a critical period of development, this dysfunction may lead to abnormal aqueductal morphology. ^8,11,12

In mice, mutations in Hydin, Pcdp1, and Mdnah5 genes determine abnormal ciliary function and prenatal hydrocephalus. ^8,11,12 The Mdnah5 gene is homologous of the human DNAH5 gene, mutated in some patients with primary ciliary dyskinesia. It must be mentioned that in all animal models of these genetic disorders, the type of hydrocephalus implicated is aqueductal stenosis. In human primary ciliary dyskinesia, mutations in DNAI1 and DNAH5 genes were identified earlier although others may be implicated. ¹

Six reports described 11 patients with fetal ventriculomegaly or hydrocephalus with onset in infancy, associated with primary ciliary dyskinesia ^{2 –7} : 5 cases were isolated, and 6 occurred in 2 families. Four patients had dextrocardia, situs inversus, or heart malformations; 1 fetus had a 3-lobed left lung. Hydrocephalus was diagnosed either prenatally (at 19th and 29th weeks’ gestation) or in early postnatal life (always before 5 months). Aqueductal stenosis was explicitly reported in 2 cases, ^3,4 is implicit in the report by Kosaki ² , and was also present in our patient. The other patients either were studied with CT but all that is mentioned is “enlarged lateral ventricles” ⁵ or the diagnosis of hydrocephalus was based on fetal ultrasound and were reported without information on the type of hydrocephalus. ⁶ We did not have access to the report by Picco et al. ⁷

One study estimated the incidence of fetal/congenital hydrocephalus at 0.82 out of 1000 live births. ¹³ Others have found a lower incidence of 0.46 out of 1000, but hydrocephalus associated with neural tube defects was not included. ¹⁴ Developmental anomalies stand as the major cause of fetal hydrocephalus, and several investigators considered that aqueductal stenosis was a major cause of hydrocephalus identified at birth (33%). ^15,16 Congenital hydrocephalus is genetic in 2% to 15% of cases. ¹⁷ Although X-linked hydrocephalus due to L1CAM mutations is the most commonly recognized cause, there are in the literature very rare cases of autosomal recessive ^{18 –20} and 2 reports of families with apparently autosomal dominant ^21,22 hydrocephalus with aqueductal stenosis. One family with autosomal dominant hydrocephalus had in addition a situs inversus anomaly. ²¹

Several reports on the outcome of a considerable number of children with a previous diagnosis of isolated fetal ventriculomegaly did not identify patients with ciliary dyskinesia. ²³ Moreover, all patients with hydrocephalus and primary ciliary dyskinesia previously described had heterotaxy and/or heart malformations. It is therefore unlikely that primary ciliary dyskinesia is responsible for a considerable number of cases of isolated unexplained hydrocephalus.

We think that our patient and others previously reported nevertheless constitute evidence for a rare etiology of prenatal or early-onset postnatal, autosomal recessive hydrocephalus.

The diagnosis of primary ciliary dyskinesia–associated hydrocephalus should be considered when fetal ventriculomegaly or hydrocephalus with aqueductal stenosis at birth or in early life are found in association with heterotaxy or heart malformations and/or a genetic autosomal recessive pattern of inheritance is likely.

Finally, evidence that ciliary dyskinesia may be implicated in aqueductal stenosis is 1 interesting hypothesis on the pathophysiology of hydrocephalus.