Hypotrichosis-Lymphedema-Telangiectasia-Renal Defect Syndrome

A number sign (#) is used with this entry because of evidence that hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (HLTRS) is caused by heterozygous mutation in the SOX18 gene (601618) on chromosome 20q13.

Biallelic mutations in the SOX18 gene result in hypotrichosis-lymphedema-telangiectasia syndrome (HLTS; 607823), which has overlapping features with HLTRS.

Description

Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome is an autosomal dominant disorder characterized by these 4 features, which begin in early childhood and are progressive (summary by Moalem et al., 2015).

Clinical Features

Sherwood et al. (1987) described an English family in which the father and his only son, aged 4 years, had an unusual association of uncommon facies, including telangiectasia in a butterfly distribution, similar skin lesions on extensor surfaces, sparse hair, and membranoproliferative glomerulonephritis. Eyebrows and eyelashes were sparse. The son had had pyloric stenosis. The father had been found to have a dermatologic disorder of uncertain nature at the age of 22 years; by the age of 30, he was in end-stage renal failure. Electron microscopy of renal biopsies showed focal subendothelial deposits of electron-dense granular material in the glomeruli. The father underwent renal transplantation at the age of 33.

Irrthum et al. (2003) reported a boy who had sparse hair at birth and presented with swelling of the upper eyelids, scrotal edema, and very large bilateral hydroceles. Hair loss began at approximately 6 months of age, accompanied by a lightening of hair color. Alopecia was almost complete, including eyebrows and eyelashes, at about 6 years of age. The patient also had mild eczema on the cheeks and telangiectases on the scalp, scrotum, and legs; nails and teeth were normal. His brother had died in utero at 30 weeks' gestation. The fetus had nonimmune hydrops fetalis, with chylous effusions in the pleural and peritoneal cavities. The lungs showed generalized vascular congestion and a mild dilatation of lymphatic vessels; postmortem examination showed pulmonary lymphangiectasia. The parents were unrelated and unaffected. Moalem et al. (2015) reported follow-up of the proband of the family reported by Irrthum et al. (2003). At age 5 years, he developed renal failure and severe hypertension. Renal biopsy showed a chronic microangiopathy, and electron microscopy showed microvillous hyperplasia and effacement of foot processes. The renal dysfunction was slowly progressive, necessitating renal transplant at age 14 years. Moalem et al. (2015) noted that the patient had dysmorphic features, including puffy eyelids, broad nasal root and tip, full lips, and prognathism.

Proesmans et al. (1989) reported a 10-year-old Belgian boy with sparse hair, absent eyebrows and eyelashes, and skin abnormalities including mild epidermal hyperkeratosis, reduced levels of subcutaneous fat, cutaneous telangiectases, and dense freckles in a butterfly distribution. He had a 2-year history of proteinuria and arterial hypertension. Renal biopsy showed membranoproliferative glomerulonephritis with normal serum complement levels. He had an unusual facial appearance, with oval face, prognathism, and long nose with high nasal bridge. He also had mild developmental delay. The paternal grandmother and a great aunt were reported to have absent eyebrows and eyelashes and hypertension. Proesmans et al. (1989) noted the phenotypic similarities to the father and son reported by Sherwood et al. (1987). Moalem et al. (2015) reported follow-up of the patient reported by Proesmans et al. (1989), noting that he was born with a hydrocele. Additional facial features included puffy eyelids and long, narrow nose with broad nasal tip and root. He developed progressive chronic renal failure in his late teens, necessitating renal transplantation at age 27 years. Radiographs showed calcified choroid plexus and renal artery arteriosclerosis, suggestive of premature aging. He did not have peripheral lymphedema.

Inheritance

The transmission pattern of HLTRS in the family reported by Sherwood et al. (1987) was consistent with autosomal dominant inheritance.

Molecular Genetics

In 2 brothers originally diagnosed with HLTS, Irrthum et al. (2003) identified a heterozygous nonsense mutation in the SOX18 gene (C240X; 601618.0003). The father was unaffected, suggesting gonadal mosaicism. Moalem et al. (2015) reported that the surviving brother reported by Irrthum et al. (2003) had developed renal failure, and proposed that the diagnosis be revised to HLTS with renal defect (HLTRS). Functional studies were not performed, but Moalem et al. (2015) postulated a dominant-negative effect.

In the patient with HLTRS reported by Proesmans et al. (1989), Moalem et al. (2015) identified a de novo heterozygous C240X mutation in the SOX18 gene.

History

Shultz et al. (1991) reported a mouse mutation called 'hairpatches' (Hpt), characterized by pigmentation abnormalities and progressive glomerulosclerosis resulting in renal failure, and stated that the disorder was similar to that reported in humans by Sherwood et al. (1987) and Proesmans et al. (1989). The Hpt locus was mapped to mouse chromosome 4. Thus, according to the suggestion of Shultz et al. (1991), 9p would be a plausible location for a homologous condition in humans. However, Hosur et al. (2013) determined that the Hpt mouse results from a heterozygous mutation in the Tal1 gene (187040).