A novel MPLKIP‐variant in three Finnish patients with non‐photosensitive trichothiodystrophy type 4

Trichothiodystrophy is a group of multisystem neuroectodermal disorders with dysplastic hair as the cardinal symptom. We describe three patients from two Finnish families in whom whole‐exome sequencing revealed a novel homozygous variant, c.26del, p.(Pro9Glnfs*144) in the MPLKIP‐gene, confirming the diagnosis of non‐photosensitive trichothiodystrophy type 4 (TTD4). The variant was confirmed by Sanger sequencing and inherited from unaffected carrier parents. This report adds to the literature by expanding the genetic and phenotypic spectra of MPLKIP‐related trichothiodystrophy. We describe dysmorphic features in the patients and provide a comparison of clinical characteristics in patients with TTD4 reported to date.


| INTRODUCTION
Trichothiodystrophy (TTD) is an ultra-rare, autosomal recessive neurocutaneous disorder described in 1968 (Pollitt, 1968). The name TTD refers to a group of disorders characterized by sulfurdeficient, brittle hair, giving rise to a characteristic alternating light and dark appearance called "tiger tail banding" of the hair under polarizing microscopy (Liang, 2005). In addition to the dysplastic hair, the diagnostic hallmark of the disorder, patients with TTD may exhibit a variety of associated features, including intellectual disability, growth retardation, ataxia, seizures, ichthyosis, and hypogonadism (Table 1).
TTD is divided into photosensitive and non-photosensitive forms.
About half of the patients have photosensitive TTD, a nucleotide excision repair (NER) disorder causing cellular and clinical hypersensitivity to UV light. These individuals have variants in transcription factor IIH (TFIIH) subunit genes. In the non-photosensitive form of TTD, however, patients lack cutaneous photosensitivity and are NER proficient. MPLKIP (M-phase-PLK1-interacting protein, MIM 60918, synonyms TTDN1, C7orf11) was the first causative gene identified as underlying non-photosensitive TTD and causes TTD4 (MIM 234050) (Nakabayashi, 2005). Recently, the genes RNF113A, GTF2E2, and TARS1 were identified as causing other non-photosensitive TTD subgroups (TTD5-TTD7). For some patients, the molecular cause is unknown (Theil, 2019).
Here, we report clinical, molecular, histological, and imaging data on three Finnish patients from two families with non-photosensitive TTD4, caused by a novel homozygous variant in MPLKIP.

| PATIENTS
The probands were three girls from two separate families, born to nonconsanguineous Finnish parents (Figure 1). The families are not known to be related but reside in the same geographical region in Western Finland, suggesting a founder effect in this region that previously acted as a genetic isolate and where some autosomal recessive conditions are enriched (Varilo, 1996). The older sister from Family 1 (Proband II-3, Figure 1(a)) was born at term after an uneventful pregnancy with normal birth size (birthweight 3560 g, length 50 cm, head circumference 33 cm). She had global developmental delay and was later diagnosed with mild intellectual disability. She reached independent walking at age 26 months. She had ataxia with onset before the age of 2 years. As a child, she exhibited stereotypic hand movements. She also had epilepsy and later became seizure-free with a normal follow-up electroencephalogram (EEG). On one occasion in early childhood, she temporarily lost all hair on her scalp. She grew slowly, with delayed bone age and late puberty. Her head circumference (hc) was −3 standard deviations (SD).
At age 18 years, she was 163.5 cm tall, corresponding to −0.6 SD (the mid-parental height was 0.8 SD).
At examination, epicanthus, long nose, short philtrum, full lips, high-arched palate, low hanging columella, hypoplastic alae nasi, long palpebral fissures (giving an impression of large eyes), sparse eyebrows, and low-set ears were noted. Her hair was dysplastic, with occasional patchy hair loss on the scalp. She had pes planovalgus, sandal gap, slender extremities and fingers, thoracic scoliosis, and kyphosis. The skin was dry with keratosis pilaris, the nails were slightly dysplastic, longitudinally ridged, and distally brittle. Brain magnetic resonance imaging (MRI) and computer tomography of the brain were normal. Dental examination was unremarkable. Ophthalmological examination showed restricted peripheral visual fields.
The younger sister from Family 1 (Proband II-4, Figure 1) was born at term after a normal pregnancy and with normal birth size (birthweight 3325 g, length 49.5 cm, hc 32 cm). In infancy, feeding difficulties and hypotonia were noted, and she had an episode of hair loss. Like her sister, she exhibited stereotypic hand movements in childhood. She had developmental delay and was later diagnosed with mild intellectual disability. She reached independent walking at age 18 months and produced words at age 2 years. She had ataxia with onset before the age of 2 years. She had no seizures. She had delayed bone age and growth retardation. At age 16.5 years her height was 149.3 cm (−2.9 SD), well below the mid-parental height (0.8 SD). Her hc was small, −3 SD. She received hormone treatment for delayed puberty due to hypergonadotropic hypogonadism.
At examination, she had short philtrum, low hanging columella, high-arched palate, hypoplastic alae nasi, and long palpebral fissures (giving an impression of large eyes). She also had thoracic kyphosis, dry palmar skin, pes planovalgus, and sandal gap. The nails were longitudinally ridged and brittle and the hair dysplastic. Brain MRI at age 2 years was normal except for somewhat delayed myelination. EEG was normal. An MRI scan of the abdomen visualized only one ovary.
The third patient (Proband II-1 from Family 2, Figure 1(a)) was born at term following a pregnancy complicated by gestational diabetes. Her birth size was normal (birthweight 3120 g, length 49.5 cm, hc and hair shaft abnormalities typical of TTD (Figure 1(b)-(e)).

| DISCUSSION
The MPLKIP-gene encodes a 179 amino-acid protein comprising two exons. Its function is largely unknown, although it has been suggested to play a role in the maintenance of cell cycle integrity, and in regulating mitosis and cytokinesis (Nakabayashi, 2005;Zhang, 2007 fibroblasts, consistent with the TTD phenotype (Nakabayashi, 2005).
Among the pathogenic MPLKIP-variants causing TTD4 (Table 1), most are protein-truncating, like the variant in our patients.
To evaluate genotype-phenotype relationships in TTD4, we compared clinical features among patients with MPLKIP-variants published to date (Table 1). In line with earlier reports, we observed no genotype-phenotype correlations (Botta, 2007;La Serna-Infantes, 2018). As is evident from Table 1, TTD4 is a multisystem disorder. For unknown reasons, most patients have shown growth retardation. Our patient had growth-hormone deficiency, which is, to the best of our knowledge, not described before in TTD4, although reported occasionally in photosensitive TTD (Atkinson, 2014).
Although no distinct facial gestalt has been described, facial dysmorphism is frequently reported in TTD4.
In summary, we report three Finnish patients in two families with a novel variant in MPLKIP causing TTD4. This report adds to the literature by expanding the allelic and phenotypic spectra of this ultra-rare disorder.

ACKNOWLEDGMENTS
The late Docent Mirja Somer is warmly remembered and thanked for inspiration and support in recognizing, 12 years ago that this was a recessively inherited clinical entity with discernible dysmorphic features and a likely founder variant in this particular subpopulation. We thank the patients and their parents for allowing the publication of their data. CENTOGENE is gratefully acknowledged for identifying the variant and for kindly providing us with technical data during manuscript preparation.