Xeroderma Pigmentosum-Trichothiodystrophy overlap patient with novel XPD/ERCC2 mutation
A 25-y old male () was referred with dry skin, lentigines, cutaneous warts and dysmorphic features. He was conceived by healthy, non-consanguineous Caucasian parents and born after an uneventful pregnancy. At the age of three, he was diagnosed with strabismus and hypermetropia and since 12 y of age he used hearing aids because of sensorineural hearing loss. Since early childhood the patient suffered from very dry skin and became easily sunburned despite preventive measures although he never developed blisters. From early puberty he gradually developed many freckles, sparse, thin hair, photophobia and growth retardation ().\nHe had an older brother who died at age 26 due to ruptured appendicitis and salmonella sepsis. The deceased brother had a similar phenotype with short stature, ichthyosis, hypogonadism, epilepsy, mild mental retardation and diabetes mellitus. A second brother and a sister displayed none of these traits and were considered healthy. The patient’s height was 165 cm (healthy siblings had a height between 180 and 200 cm). Medical history, clinical examination and laboratory and imaging test revealed diseases in many organs.\nHe had dry, parchment-like skin with ichthyosiform scaling mainly on the back and scattered, but pronounced, lentiginous pigmentation (). Viral warts were seen on his hands, knees and feet. He had sparse, brittle and unruly hair and koilonychia with distal nail splitting (). Hair microscopy showed some variation in the calibre of the hair shafts with few trichorrhexis nodosa-like defects. Some hairs had focal ribboning/undulation and irregular contours. No “tiger-tail pattern” was observed using polarizing light microscopy. Cystine content in hair was only slightly decreased to 8.2 mol% (normal values 10.0−10.5 mol%, analysis performed by Dr Josef Föhles, Aachen, who provided reference values). At the age of 28, basal cell carcinoma was diagnosed on his shoulder.\nEye examination revealed photophobia and severely decreased visual acuity (1/60 on the right eye and 12/60 on the left eye) (). He had esotropia but no nystagmus. He had bilateral microphthalmos with an axial length of 18.39 mm on the right eye and 18.53 mm on the left eye, but normal corneal size (12 mm on both eyes). He had hypopigmentation of the iris with transillumination. Corneas were normal with the exception of limbal vascularization. Before cataract surgery he had an excessive hyperopia +13 D on both eyes. He had bilateral cataract with punctate lens opacities. Ophthalmoscopy revealed hypopigmentation of the retina, tortuosity of the vessels and macular lesions with pigment epithelial derangement and atrophy, retinal fibrosis and macular folds on both eyes. Earlier performed visual evoked potential (VEP) was normal and electroretinography did not show any signs of tapetoretinal degeneration.\nHe had a high-pitched voice, micropenis (2 cm) and cryptorchidism with high levels of plasma luteinizing- and follicle stimulating hormones and very low plasma testosterone. Pubic and axillary hairs were absent. Type 2 diabetes was diagnosed at the age of 26 and required insulin treatment. The pituitary-adrenal axis and thyroid function were normal.\nNeurologic examination showed progressive ataxia and a broad-gauged gait. Varying imaging studies showed thickened theca cranii and a dysmorphic sella turcica as the only clear-cut abnormal findings and EEG was normal. Multiple CT scans as well as an MRI of the cerebrum were normal at around age 27.\nBetween ages 25 to 31, he developed progressive renal disease with an increase in P-creatinine from 114 to 252 µmol/l, persistent albuminuria around 1.0 g/l and intermittent hematuria. Renal biopsy revealed partial atrophy and sclerosis with scattered hyaline tubular casts but immunoflourescent evaluations were all negative. Electron microscopy showed expanded mesangium and unevenly thickened glomerular basement membranes with varying density but without deposits. The renal disease was complicated by nephrogenic anemia, renal osteodystrophy and arterial hypertension. MCV was low, but within normal range and HBa2 was not tested. Due to hypercholesterolemia treatment with Simvastatin was initiated but had to be discontinued due to acute renal failure caused by rhabdomyolysis. Kidney function was restored after three weeks on dialysis.\nMitochondrial function was normal when respiratory enzymes were measured in a liver biopsy. Plasma concentrations of amino acids were normal except for a slight elevation of P-cysteine. A biopsy from striated muscles did not reveal any primary muscular disorder.\nDue to recalcitrant viral warts and frequent pneumonias, a lymphocyte-subpopulation evaluation was conducted showing normal fractions and concentrations of T-, B- and NK-cells. CD4+ count was slightly below normal levels and CD4+/CD8+ levels inversed T- and B- memory cell levels were unexpected high, mimicking levels of a much older person. It was concluded that the patient was slightly immunodeficient.