Hypotrichosis-Lymphedema-Telangiectasia Syndrome

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

Heterozygous mutation in the SOX18 gene causes the related disorder HLTS with renal defect (HLTRS; 137940).

Description

Hypotrichosis-lymphedema-telangiectasia syndrome is an autosomal recessive disorder characterized by these 3 features, which begin at birth or in early childhood and are progressive (summary by Irrthum et al., 2003).

Clinical Features

Irrthum et al. (2003) described 2 families with an unusual association of hypotrichosis, lymphedema, and telangiectasia. In the first family, previously reported by Devriendt et al. (2002), a boy and girl, offspring of first-cousin Belgian parents, were affected. The boy was born at 32 weeks' gestation and presented with respiratory distress. A normal amount of scalp hair was present at birth but decreased progressively to the extent of total alopecia at age 6 months. The hair remained very sparse with absent eyebrows and eyelashes; sweating, nails, and teeth were normal. The skin over the hands and feet was thin and transparent, with visible blood vessels. Bilateral hydrocele was surgically corrected at age 12 years. Beginning at approximately 15 years of age, the patient progressively developed lymphedema of the legs. At 25 years of age, a doppler ultrasonogram of the venous system of the legs was normal. At that time, however, lymphatic scintigraphy with radiolabeled tracer showed no evidence of lymphatic flow from the dorsum of the foot. His younger sister presented with a similar phenotype. At birth she had normal black hair. A vascular nevus was present on the palm of the right hand and faded during childhood. During infancy, her hair diminished progressively, and from approximately 2 years of age her hair was very sparse with no eyebrows or eyelashes, and she did not develop axillary or pubic hair at puberty. Around puberty, she developed progressive lymphedema of the legs. At age 26 years she showed normal teeth, nails, and sweating, but her skin was thin. The skin over her hands and feet was transparent, and dilated veins and varicosities were apparent on the palm of her right hand. The single affected individual in the second family studied by Irrthum et al. (2003) was a 12-year-old girl, the offspring of unaffected first-cousin Turkish parents, who had previously been described in detail by Glade et al. (2001). Lymphedema of the legs appeared at age 4 years. Scalp hair had always been sparse; eyebrows and eyelashes were missing. Palms and soles showed multiple telangiectases, with ectatic capillaries and cutis marmorata-like lividity of the skin.

Wunnemann et al. (2016) reported a 13-year-old girl who had hypotrichosis and diffuse striking livedo reticularis noted from birth, as well as dysplastic toenails and cutis marmorata. She developed hypertension at 18 months of age, and was diagnosed with severe dilation of the ascending aorta at 2 years of age. Repeat echocardiograms showed progression of the aortic dilation over the next decade. Renal angiography was normal at age 3 years, and renal function remained intact. She did not exhibit lymphedema; histopathologic examination of skin biopsies from areas of livedoid erythema showed the typical appearance of malformed telangiectatic small vasculature, and immunohistochemical analysis confirmed the severe dilation of small blood vessels, with an intact lymphatic vascular network. The authors noted that the manifestation and onset of lymphedema in HTLS is highly variable. They suggested that in addition to environmental factors and/or genetic background, treatment with high doses of the nonspecific beta-blocker propranolol throughout childhood also might have had an effect in preserving lymphatic function in this patient.

Inheritance

The transmission pattern of HLTS in the families reported by Irrthum et al. (2003) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of 2 consanguineous families with HLTS, Irrthum et al. (2003) identified 2 different homozygous missense mutations in the SOX18 gene (A104P, 601618.0001 and W95R, 601618.0002, respectively). Both mutations affected the DNA-binding domain, but functional studies of the variants were not performed.

In a 13-year-old girl with hypotrichosis, telangiectasia, and dilation of the ascending aorta, who did not exhibit lymphedema, Wunnemann et al. (2016) performed whole-exome sequencing and identified heterozygosity for a de novo nonsense mutation in the SOX18 gene (Q161X; 601618.0004). The authors considered the findings in this patient to expand the clinical spectrum of HTLS.

Animal Model

In embryos of the naturally occurring Sox18-mutant mouse strain ragged-opossum (RaOp), Downes et al. (2009) demonstrated that early genesis and patterning of vasculature was unimpaired, but surface capillaries became enlarged from 12.5 days postcoitum, and that embryos developed massive surface hemorrhage by 14.5 days postcoitum. Large focal breaches in the endothelial barrier were observed, in addition to endothelial hyperplasia associated with impaired pericyte recruitment to the microvasculature. Expression of the genes encoding the endothelial factors MMP7 (178990), IL7R (146661), and N-cadherin (CDH2; 114020) was reduced in RaOp embryos, suggesting that these may be downstream targets of SOX18. Downes et al. (2009) hypothesized that vascular anomalies in HLTS arise from defects in regulation of genes required for the acquisition of structural integrity during microvascular maturation.