A 44-year-old Japanese man was referred to our hospital with various systemic symptoms that had gradually developed since infancy. His parents were non-consanguineous, and there was no family history of similar symptoms. He had a medical history of dysphagia and dysarthria from around the age of 35 years, and hearing loss occurred at approximately 40 years of age.

Dermatological and orthopedic examinations revealed several characteristic manifestations. The patient had a short stature (149 cm) and presented with muscle weakness in all extremities. Poikiloderma with mottled pigmentation and telangiectasia was remarkable on the face (Figure 1A). The eyebrows and eyelashes were almost absent, and lagophthalmos due to skin sclerosis was observed (Figure 1B). Scalp hairs were also sparse, and the top of the head had been almost hairless since childhood (Figure 1C). The trunk and extremities showed dry skin, mild eczema, small pigmented macules, and skin sclerosis (Figure 1D). He had mild lymphedema of the lower limbs and a medical history of cellulitis due to this symptom. His left heel could not be placed on the ground due to Achilles tendon contracture, resulting in a constant flexed position of his left knee (Figures 1E,F). Mild hypoplasia of the hands and feet, multiple calluses on the soles, and impaired extension of the fingers were noted (Figures 1G–I). Histology of the non-sun-exposed skin showed epidermal atrophy and mild dermal fibrosis (Figure 1J). Fragmented elastic fibers were clearly observed with Elastica–Masson staining (Figure 1K). Muscle magnetic resonance imaging (MRI) findings showed severe fatty infiltration in the bilateral quadriceps muscles (Figure 1L), erector spinae muscles, and muscles in the upper extremities.

Further examinations revealed interstitial pneumonia, liver cirrhosis, and chronic kidney disease. A chest computed tomography (CT) scan revealed interstitial lung shadows, predominantly in the upper lobes, indicating the cause of his shortness of breath. His liver cirrhosis was graded as Child–Pugh class B and was accompanied by portal hypertension and esophageal varix. In this case, liver cirrhosis was diagnosed based on the findings of CT and ultrasonography, since a biopsy could not be performed. Ophthalmological examination revealed the presence of retinal rod dysfunction, lacrimal passage obstruction, and ptosis, but not cataract. Otolaryngological examination revealed atrophied vocal cords and mild sensorineural hearing loss.

Based on the clinical findings described above, a diagnosis of POIKTMP was highly suspected. To confirm this, mutation analysis of FAM111B was performed. The patient and his parents provided written informed consent to participate in this study, in compliance with the Declaration of Helsinki. The Institutional Review Board at Hokkaido University Graduate School of Medicine approved this study (project no. 14–063). In brief, genomic DNA was extracted from peripheral blood using the QIAamp DNA Blood Maxi Kit (Qiagen, Hilden, Germany), and all exons and exon–intron boundaries of FAM111B were amplified using polymerase chain reaction (PCR). The PCR products were sequenced using an ABI 3130xl Genetic Analyzer (Applied Biosystems, Foster City, CA, United States), which led to the identification of a novel and de novo heterozygous missense mutation c.1886T > G (p(Phe629Cys)) (RefSeq accession number NM_198,947.4) in the patient (Figures 2A,B). This mutation was absent in 96 unrelated Japanese controls and in databases, such as the 1000 Genomes Browser, the Single Nucleotide Polymorphism Database, the Human Genetic Variation Database, and gnomAD. Notably, the position of the mutation was very close to that of other pathogenic mutations previously reported (Figure 2C), and the amino acid residue affected by this missense mutation was conserved among mammals (Mercier et al., 2015), suggesting the importance of the residue in the function of FAM111B. The pathogenicity was also estimated using in silico algorithms; PolyPhen2 (probably damaging), PROVEAN (deleterious), SIFT (damaging), and CADD score (25.4). Furthermore, it is classified as pathogenic also according to the ACMG guideline. Conversely, although RECQL4, the causative gene of Rothmund–Thomson syndrome (RTS) (which is the most common differential diagnosis), was also analyzed, no pathogenic mutations were detected in the patient (data not shown). These findings verified the diagnosis of POIKTMP, making this the first case in Japan.

At the age of 47 years, his shortness of breath and interstitial lung shadows on chest CT worsened compared to those at 44 years of age (Figures 3A,B) immediately after recovery from bacterial pneumonia. His oxygen saturation was 94% in ambient air. Bilateral fine crackles were detected predominantly in the right upper fields on chest auscultation. Pulmonary function tests showed a restrictive ventilatory impairment (vital capacity [VC], 1.56 L; VC % predicted, 45.7%) and a decline in diffusing capacity (diffusing capacity for carbon monoxide % predicted [DLCO % predicted], 42.6%). The ratio of residual volume to total lung capacity was elevated (38.1%), indicating the presence of respiratory muscle weakness. Serum levels of Krebs Von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) were elevated to 1,085 U/mL, 98.3 ng/ml, 505.6 ng/ml, respectively. Bronchoalveolar lavage (BAL) from the right upper lobe (B³b) revealed an increased proportion of neutrophils and eosinophils (macrophages, 82.0%; lymphocytes, 7.0%; neutrophils, 6.7%; eosinophils, 4.3%; CD4/CD8 ratio, 0.66) in the BAL fluid. Echocardiography results were within the normal limits. Based on these findings, an exacerbation of interstitial pneumonia was considered, and 40 mg/day of prednisolone was administered. 2 weeks later, his shortness of breath, interstitial shadows on the chest CT scan (Figure 3C), and markers of interstitial pneumonia improved. Serum levels of SP-A and SP-D decreased (62.9 ng/ml and 321.4 ng/ml, respectively), although serum KL-6 unchanged. Pulmonary function tests showed improvements in %VC and %DLCO (49.5 and 54.5%, respectively). However, shortly thereafter, he abruptly developed severe hepatic encephalopathy. Although he temporarily recovered after treatment with amino acid preparation and lactulose, there was no more effective treatment since he was already in a phase of hepatorenal syndrome. He finally developed severe hypoxemia due to worsening of bilateral pneumonia and pulmonary edema, which led to death within a few days. Subsequently, an autopsy was performed.

Pathological findings in the lungs revealed fibrotic changes with an unclassifiable pattern, predominantly in the right upper lobe (Figures 4A,B). Findings of organizing pneumonia and bacterial pneumonia with gram-positive cocci were also noted (Figures 4B,C). Pulmonary edema was observed in a large part of the lungs, and alveolar hemorrhage was seen in the right middle lobe and left lung. Liver tissue showed fibrosis and steatosis (Figure 4D), but findings indicative of nonalcoholic steatohepatitis were not observed. Kidney tissue showed interstitial fibrosis, glomerular sclerosis, and tubular atrophy (Figure 4E). Skeletal muscles and the myocardium showed atrophy, fatty degeneration, and basophilic degeneration (Figures 4F,G). Pancreatic tissue showed severe atrophy and fatty infiltration with scarce exocrine glands. Thyroid tissue showed atrophy and interstitial fibrosis (Figure 4H). Laryngeal tissue showed atrophy and degeneration in the cricothyroid and thyroarytenoid muscles, which led to vocal cord atrophy. The testis tissue showed atrophy of seminiferous tubules, indicating male infertility (Figure 4I).