1 Introduction
Neurofibromatosis (NF) is an autosomal dominant genetic disease [
1]. NF type 1 (NF1), which is caused by mutations in the
NF1 gene, can be characterized by café-au-lait macules, freckles, Lisch nodules, peripheral neurofibromas, optic gliomas, and other neurological abnormalities, such as cognitive defects [
1–
3]. Cases of NF1 with pulmonary involvement are rare [
2], and chest computed tomography (CT) performed on NF1 patients most frequently detects bilateral basal reticulations, apical bullae, and cysts [
2,
4].
Most primary ciliary dyskinesias (PCDs) are considered as autosomal recessive disease whose estimated prevalences among live-born children are approximately 1:10 000 to 1:20 000 [
5]. Over 40 genes have been determined to be related to PCD [
6,
7]. Related gene mutations cause structural or functional abnormalities in cilia, leading to bronchitis, bronchiectasis, sinusitis, otitis media, infertility, and hydrocephalus [
5,
7,
8]. Over 75% of full-term neonates with PCD have “neonatal respiratory distress” (few are diagnosed with PCD at this age), and most children have chronic year-round wet cough, sputum production, and chronic wheezing [
9], as well as chronic airway infection resulting in bronchiectasis in most cases [
9]. Thus far, no single gold-standard diagnostic test for PCD has been developed [
5,
8].
Cases with PCD combined with NF are extremely rare, and to the best of our knowledge, only one similar case had been previously reported [
10]. We hope that our case can be helpful in the differential diagnosis of rare diseases with pulmonary involvement.
2 Case presentation
A 21-year-old man who had been diagnosed with NF presented to our hospital complaining of productive cough since he was 2 years old and shortness of breath for approximately one year and a half. In his past medical history, he had a fever with maximum body temperature of 38 °C after birth, accompanied by wheezing in the throat while drinking milk. Thus, his ailment was diagnosed as “aspiration pneumonia,” and his condition improved after receiving antibiotics. He had no history of tuberculosis or measles infection. His parents were not in a consanguineous marriage. Both his parents and his younger brother are in good health, without respiratory symptoms and infertility. Rhonchi could be heard in his lungs. He did not show cyanosis or digital clubbing. Pseudomonas aeruginosa was detected from his bronchial aspiration. Chest high-resolution computed tomography showed bronchiectasis in the right middle lobe and multiple centrilobular micronodules in both lungs; the micronodules were predominantly distributed on the right side, forming the tree-in-bud structure (Fig. 1).
Aside from respiratory symptoms, the patient also suffered from mental retardation, memory loss, walking instability, and café-au-lait macules in the skin (Fig. 2). Head magnetic resonance imaging revealed expansion of the supratentorial ventricular system (Fig. 3), and the proximal midbrain aqueduct may have adhered, causing obstructive hydrocephalus.
Several tests were performed upon admission to obtain an exact diagnosis. His bronchial mucosa was examined via transmission electron microscopy, which clearly showed that the ciliated microtubule ultrastructure was abnormal. Deficiency of central microtubules, radial spoke, and peripheral microtubule deletion were detected, which led to the formation of central microtubule displacement, “9+ 0” arrangement, and “8+ 2” arrangement (Fig. 4), which are typical of mutations in radial spoke proteins and consistent with PCD. In addition, his sinus CT indicated sinusitis. Semen analysis revealed that the total sperm number and semen density were 39.03×10
6 and 12.59×10
6/mL, respectively. Among them, grade A, grade A+ B, grade A+ B+ C, and grade D sperm accounted for 2.82%, 5.16%, 8.92%, and 91.08%, respectively, revealing that most of the sperm was immobile. He was diagnosed via whole-exome sequencing performed on the Illumina HiSeq XTen platform. The reads were aligned to the Genome Reference Consortium Human Build 37 (GRCh37/hg19) human assembly by using the Burrows–Wheeler Aligner. Results showed a homozygous mutation, c.667delA, p.S223Afs*15, in the
RSPH4A gene, which is associated with PCD [
6,
7,
11,
12]; and a heterozygous mutation, c.730+ 1G>A, in the
NF1 gene, supporting the diagnosis of NF1 [
2] (Fig. 5). All mutations were confirmed by Sanger sequencing.
RSPH4A, whose mutation can be found in patients with PCD, is a gene-encoded radial spoke head protein associated with cilia–axoneme defects, causing clinical features of respiratory disease similar to those seen in patients with PCD with “classic” dynein arm defects [
11,
12].
Unfortunately, the patient and his family refused to continue treatment because they lacked financial resources. Eventually, he died at the age of 27 years due to respiratory failure caused by pulmonary infection. The patient’s medical timeline is shown in Fig. 6.
3 Discussion
At the time of admission, the patient was diagnosed with NF, which led us to think that the first consideration of the causes of his lung disease was NF. However, according to the literature, the chest CT of patients with NF with lung involvement presents as bilateral basal reticulations, apical bullae, and cysts [
2,
4]. The predominant bronchiectasis manifestation cannot be explained by his NF diagnosis on the chest image. Therefore, we attempted to make a differential diagnosis of his bronchiectasis.
Combined with the early-onset year-round wet cough, sinusitis, and sperm quality decline, we considered the possibility of diagnosing the patient with PCD. Further electron microscopy analysis and identification of homozygous mutations in the RSPH4A gene confirmed the diagnosis of PCD. Given that these two gene loci are not adjacent and are unlikely to mutate at the same time, this phenomenon may be an episodic one.
Furthermore, patients with NF1 may have optic pathway gliomas or other central nervous system tumors that may cause obstructive hydrocephalus [
13]. However, no tumor was found in his head magnetic resonance imaging as the cause of the hydrocephalus observed in this patient. Therefore, we considered that the ependymal cilia dysfunction caused by PCD may be the reason for the hydrocephalus.
Regrettably, his family was unable to support his continued treatment because of the lack of financial resources. Unfortunately, he died of lung infection 6 years later. This outcome warns us that patients with PCD must be carefully investigated and properly treated; otherwise, it may lead to serious health consequences or even death of the patient.
This case report emphasized that when an image change exists in the lungs (or other symptoms) that does not correspond to the primary disorder (in this case, NF), the possibility of other diagnoses must be considered, and PCD is one of the respiratory disorders that should be prioritized in such cases.
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